Aminoalkoxybenzoyl-benzofuran or benzothiophene derivatives, method for preparing same and compositions containing same

ABSTRACT

The invention relates to benzofuran or benzothiophene derivatives of general formula: 
     
       
         
         
             
             
         
       
     
     These compounds are of use as medicinal products, in particular in the treatment of pathological syndromes of the cardiovascular system.

The present invention relates, in general, to novel heterocyclicderivatives and also to the process for the preparation thereof.

In particular, the invention relates to novel benzofuran orbenzothiophene derivatives which can be represented by the generalformula:

and also to their pharmaceutically acceptable salts, in which formula:

-   A represents —O—, —S— or

-   B represents a linear or branched C₁–C₅ alkylene group optionally    substituted with a hydroxyl group,-   T represents hydrogen or a C₁–C₄ alkyl radical-   R represents    -   the cyano or hydroxymethyl group    -   an oxime group of formula:        R₄—O—N═CH—    -    in which R₄ represents a C₁–C₄ alkyl group    -   a carboxyl group of general formula:

-   -    in which R₅ represents hydrogen or an alkali metal atom, a        linear or branched C₁–C₁₀ alkyl group or a C₃–C₆ cycloalkyl        group, or R₅ represents the group of general formula:

-   -    in which r represents 1 to 4    -   a carboxyl group of general formula:

-   -    in which R′₅ represents a piperidinyl group optionally        N-substituted with a C₁–C₄ alkyl group or one of the groups of        general formula:

-   -    in which R₆ and R₇, which may be identical or different,        represent a C₁–C₄ alkyl group, R₈ represents a linear or        branched C₁–C₆ alkylene group, and R₉ represents hydrogen, an        alkali metal atom or a C₁–C₄ alkyl group,    -   an aminocarbonyl group of formula:

-   -    in which R₁₀ represents hydrogen, a C₁–C₄ alkyl, hydroxyl or        amino group, a group (c) above or one of the groups:

or—R₁₂—R₁₁  (g)

-   -    in which R₁₁ represents a group (a) and R₁₂ represents a C₁–C₆        alkylene radical,    -   a group of formula:

-   -    in which R₁₃ and R₁₄, which may be identical or different,        represent a C₁–C₄ alkyl radical or a C₁–C₄ hydroxyalkyl group,    -   one of the groups of formula below:

-    R₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl    group, or a group of formula;    —(CH₂)_(p)—R₁₁-    in which R₁₁ has the same meaning as previously and p represents 1    to 4,-   Am represents a nitrogenous group of formula:

-    in which:-   R₂ represents hydrogen, a linear or branched C₁–C₆ alkyl group    optionally substituted with a hydroxyl group, a group (m), a C₃–C₆    cycloalkyl group or a benzyl group,-   R₃ represents a linear or branched C₁–C₆ alkyl group optionally    substituted with a hydroxyl group, a C₃–C₆ cycloalkyl group, a group    (m), a benzyl group or a phenyl group of formula:

-    R₁₆, R₁₇ and R₁₈, which may be identical or different, represent    hydrogen, or a hydroxyl, nitro, amino, C₁–C₄ alkoxy or C₁–C₄    alkylsulfonamido group,-   R₁₉ represents hydrogen, a C₁–C₅ alkyl group, the diphenylmethyl    group, a mono-, di- or trimethylphenyl group, a mono-, di- or    trimethoxyphenyl group, a group (a), a group (b) or a group (c),-   m and n each represent 0 or 1,-   R₂ and R₃, when they are taken together, represent a linear or    branched C₃–C₁₀ alkylene group optionally substituted with the    hydroxyl group, with a group (a) or with a group (m) and optionally    interrupted by —O—,-   these alternatives, R₂ and R₃ which are independent or R₂ and R₃    taken together, being represented in the formula (Am₁) by the symbol

-    located between R₂ and R₃-   W, W′ and Z are such that:    -   when W and W′, which are identical, represent CH, Z represents        —O— or —S—,    -   when W represents CH and W′ represents C—R₂₀, Z represents

-   R₂₀ and R₂₁ being identical or different and representing hydrogen,    a halogen atom, for example fluorine, chlorine or bromine, a C₁–C₄    alkyl radical, such as methyl, or a C₁–C₄ alkoxy radical, such as    methoxy,-   X represents —O— or —S—-   Y represents a —CO— or —CH₂— radical, or a radical of formula

-    in which R₂₂ represents hydrogen, a C₁–C₄ alkyl radical or an acyl    radical of formula:

-    in which R₂₃ represents a C₁–C₄ alkyl radical, or Y represents

-    it being understood that the combination of the R, R₁ and Am groups    contains 0, 1 or 2 groups (a), these benzofuran or benzothiophene    derivatives being in the form of individual isomers or of a mixture    thereof,-    with the exclusion of the compound methyl    2-phenyl-3-[4-(2-piperidin-1-ylethoxy)benzoyl]-benzo[b]thiophene-6-carboxylate    of formula (72) below:

Classes of preferred compounds of the invention can be represented bythe compounds of formula (1) in which:

-   either R represents an isopropoxycarbonyl group-   or Am represents a diethylpiperidino group.

Likewise, a specific class of compounds of formula I is that in which: Yrepresents a —CO— radical.

Another class of preferred compounds of formula (1) is that in which:

represents a benzoyl radical.

Likewise, a specific class of compounds of formula (1) is that in whichthe entity:

represents a 4-oxybenzoyl radical.

Likewise, the compounds of formula (1) in which X represents —O— arepreferred compounds, as are those in which the chain:-A-B—Amis located at position 4.

Finally, the compounds of formula (1) in which R₁ represents n-butyl, Brepresents a propylene group and Am represents a diethylpiperidinylgroup, in particular 3,5-diethylpiperidinyl, can also be regarded aspreferred.

Compounds of formula (1) can exist in the form of optical or geometricalisomers, for example the compounds in question in which Am represents adiethylpiperidinyl group or in which R represents an —R₄—O—N═CH— group.

Consequently, the invention relates both to the individual isomers ofthe compounds of formula (1) and to mixtures thereof, in particular theracemic mixture.

The invention also relates to the pharmaceutically acceptable salts ofthe compounds of formula (1) formed from an organic or inorganic acid.

As examples of organic salts of this type, mention may be made ofoxalate, maleate, fumarate, methanesulfonate, benzoate, ascorbate,pamoate, succinate, hexamate, bismethylenesalicylate, ethanedisulfonate,acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate,malate, cinnamate, mandelate, citraconate, aspartate, palmitate,stearate, itaconate, glycolate, p-aminobenzoate, glutamate,benzenesulfonate, p-toluenesulfonate and theophyllineacetate salts andthe salts formed from an amino acid, such as the lysine or histidinesalt.

As inorganic salts of this type, mention may be made of hydrochloride,hydrobromide, sulfate, sulfamate, phosphate and nitrate salts.

It has been found that the compounds of the invention possess noteworthypharmacological properties, in particular antiarrhythmic properties,since they have proved to be capable of suppressing or preventingdisorders of ventricular and atrial rhythm. Most of the compounds of theinvention have electrophysiological properties of classes 1, 2, 3 and 4of the Vaughan-Williams classification, which confer bradycardic,antihypertensive and anti-α-adrenergic and anti-β-adrenergic propertieswhich are noncompetitive. In addition, most of the compounds have alsodisplayed antioxidant properties, an affinity for sigma receptors and anability to enhance NO synthesis.

Moreover, these compounds of the invention demonstrate inhibitoryproperties with respect to various hormonal agents, such as, forexample, angiotensin II, arginine vasopressin, neuropeptide Y orendothelin.

These properties are capable of rendering the compounds in question veryuseful in the treatment of certain pathological syndromes of thecardiovascular system, in particular in the treatment of anginapectoris, hypertension, arrhythmia, in particular atrial, ventricular orsupraventricular arrhythmia, or cerebral circulatory insufficiency.Likewise, the compounds of the invention can be used in the treatment ofheart failure or myocardial infarction, possibly complicated by heartfailure, or for the prevention of post-infarction mortality.

In the antitumor field, the compounds of the invention may be of use aspotentiators of anticancer agents.

Consequently, the invention also relates to a medicinal product,characterized in that it comprises a compound derived from benzofuran orbenzothiophene, or a pharmaceutically acceptable salt of the latter,according to the invention.

Consequently, the invention also relates to pharmaceutical or veterinarycompositions comprising, as active principle, at least one compound ofthe invention in combination with a suitable excipient or pharmaceuticalvehicle.

Depending on the route of administration chosen, the daily dosage for ahuman weighing 60 kg will lie between 2 and 2000 mg of active principle,in particular between 50 and 500 mg of active principle.

The compounds of formula (1) can be prepared according to the followingmethods:

-   I. The compounds of formula (1) in which    -   Y represents the —CO— group    -   R₁ comprises no carboxylic or alkali metal carboxylate group    -   Am represents a group (Am₁) or (Am₂), this group comprising no        carboxylic or alkali metal carboxylate group, or Am represents a        group (Am₃) in which R₁₆ and/or R₁₇ and/or R₁₈ are different        from an amino or C₁–C₄ alkylsulfonamido group, can be obtained:

A.—When R represents a cyano or hydroxymethyl group, a group (a) inwhich R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group or else thegroup (k), by reacting, in the presence of a basic agent such as analkali metal hydroxide or carbonate, a ketone derivative of generalformula:

in which R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl orbenzyl group or a group (m) comprising no carboxylic or alkali metalcarboxylate group, T, W, W′, X and Z have the same meaning as above, A′represents OH, SH or NH₂ and R′ represents the cyano or hydroxymethylgroup, the group (k) or a —CO₂R″₅ group, in which R″₅ represents aC₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, with a compound of generalformula:R₂₄—B—Am′  (3)in which Am′ represents a group (Am₁) or (Am₂), this group comprising nocarboxylic or alkali metal carboxylate group, or else a group (Am₃) inwhich R₁₆ and/or R₁₇ and/or R₁₈ are different from an amino group or aC₁–C₄ alkylsulfonamido group, B has the same meaning as above and R₂₄represents:

either a halogen atom, such as, for example, a chlorine atom, or a C₁–C₄alkylsulfonyloxy or C₆–C₁₀arylsulfonyloxy radical, which makes itpossible to obtain, in the free base form, the desired compounds offormula I in which A represents —O— or —S—

or a halocarbonyl group, which makes it possible to obtain, in the freebase form, the desired compounds of formula (1) in which A represents

Usually, the reaction takes place at the reflux temperature of thesolvent used or at a temperature not exceeding 90° C., this solventpossibly being, for example, a polar solvent such asN,N-dimethylformamide or a ketone such as, for example, methyl ethylketone.

B.—When R represents the cyano group, an R₄—O—N═CH— group, a group (a)in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group or elsethe group (k), by reacting a compound of general formula:

in which A, B, R′₁, T, X, W, W′ and Z have the same meaning as above,and R″ represents the cyano group, the group (k), an R₄—O—N═CH— group ora —CO₂R″₅ group in which R″₅ has the same meaning as above, and Halrepresents a halogen atom, such as, for example, chlorine or bromine,with a compound of general formula:H—Am′  (5)optionally in the form of a salt, for example in the hydrochloride form,in which Am′ has the same meaning as above, the reaction taking place inthe presence of a basic agent such as an alkali metal hydroxide orcarbonate or an excess of amine of formula (5) in basic form, whichgives the desired compounds of formula (1) in the free base form.

Generally, the reaction takes place at the reflux temperature of themedium and in a polar solvent, such as N,N-dimethylformamide,acetonitrile or methyl ethyl ketone, or an apolar solvent, such asbenzene or toluene.

C.—When R represents the cyano group, an R₄—O—N═CH— group, a group (a)in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group or elsethe group (k), by reacting a compound of general formula:

in which R″, R′₁, T and X have the same meaning as above, with a halideof general formula:

in which A, B, Am′, W, W′, Z and Hal have the same meaning as above, thereaction optionally taking place in the presence of a Lewis acid, suchas aluminum chloride, stannic chloride, ferric chloride or silvertrifluoromethanesulfonate, which gives the desired compounds of formula(1) in the free base form.

Usually, the above reaction takes place in an apolar solvent such as ahalogenated compound, for example dichloromethane or dichloroethane, andat a temperature of between ambient temperature and the refluxtemperature.

Alternatively, it is possible to obtain the compounds of formula (1) inwhich the group Am represents a group (Am₁) in which R₂ and R₃ aredifferent, by converting a secondary amine of formula (1) comprising agroup (Am₁) of formula —NH—R₂, to a tertiary amine by reaction by meansof a compound of general formula:Hal-R₃  (8)in which Hal represents a halogen atom, preferably bromine, and R₃ hasthe same meaning as above, the reaction preferably taking place at thereflux temperature, in the presence of a basic agent such as an alkalimetal hydroxide or carbonate, which gives the desired compounds offormula (1) in the free base form.

The compounds of formula (1) in which R represents an oxime group offormula R₄—O—N═CH— can be in the form of stereoisomers.

The methods described above under B) and C) make it possible to obtainthese oxime derivatives in the form of mixtures of isomers. However,these isomers may be produced in separate form using known methods suchas, for example, chromatography or precipitation.

D.—When R represents the group (j), by reacting, preferably at thereflux temperature of the medium, a compound of general formula:

in which A, B, T, W, W′, X and Z have the same meaning as above, withphosgene, which gives the desired compounds of formula (1) in thehydrochloride form, which hydrochloride can be treated, if necessary,with a basic agent such as an alkali metal hydroxide or an alkali metalcarbonate, which gives the desired compounds in the free base form.

The benzofuran or benzothiophene derivatives of formula (1), which alsocorrespond to the general formula:

in which A, Am′, B, R′₁, T, X, W, W′ and Z have the same meaning asabove, are themselves synthetic intermediates for the preparation ofother compounds of formula (1) in which Y represents —CO— and Amrepresents a group (Am₁) or (Am₂), this group comprising no carboxylicor alkali metal carboxylate group, or else a group (Am₃) in which R₁₆and/or R₁₇ and/or R₁₈ are different from an amine or a C₁–C₄alkylsulfonamido group and in which R₁ comprises no carboxylic or alkalimetal carboxylate group.

To this end, the following methods, starting from the compounds offormula (10) in question, can be employed to obtain the desiredcompounds of formula (1), that is to say:

E.—When R represents a group (b) in which R′₅ represents a group (c):

a) if this group (c) is of the primary dialkylaminoalkyl type, acompound of formula (10), after protection of the amine functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted, preferably in a polar solvent, such as N,N-dimethylformamide,and usually at a temperature of between 30 and 50° C., with an alcoholof general formula:

in which R₆ and R₇ have the same meaning as above and R₈ represents alinear C₁–C₆ alkylene group, the reaction taking place in the presenceof carbonyldiimidazole and 1,8-diazabicyclo[5.4.0]undec-7-ene, and then,if necessary, the compound formed is deprotected, which gives, in thefree base form, the desired compounds of formula (1);

b) if this group (c) is of the secondary or tertiary dialkylaminoalkyltype, a compound of formula (10), after protection of the aminefunctional group when Am′ represents a group (Am₁) in which R₂represents hydrogen, is reacted, preferably in an aprotic solvent, suchas a halogenated hydrocarbon, and generally at the reflux temperature ofthe medium, with a halogenating agent, such as thionyl chloride, toobtain an acyl halide, which is subsequently treated, preferably atambient temperature, with an alcohol of formula (11) above in which R₆and R₇ have the same meaning as above and R₈ represents a secondary ortertiary C₂–C₆ alkylene group, and then, if necessary, the compoundformed is deprotected, which gives the compounds of formula (1) in thehydrohalide form or in the free base form, when the compound of formula(10) is in excess, which hydrohalide can be treated, if necessary, witha basic agent, such as an alkali metal hydroxide or an alkali metalcarbonate, to produce the desired compounds in the free base form.

F.—When R represents either a group (a) in which R₅ represents a C₁–C₁₀alkyl or C₃–C₆ cycloalkyl group or a group (b) in which R′₅ represents apiperidinyl group optionally N-substituted with a C₁–C₄ alkyl group orin which R′₅ represents a group (d) comprising no carboxylic or alkalimetal carboxylate group, a compound of formula (10), after protection ofthe amine functional group when Am′ represents a group (Am₁) in which R₂represents hydrogen, is reacted, preferably in a halogenated hydrocarbonand generally at the reflux temperature of the medium, with ahalogenating agent, such as thionyl chloride, to produce an acyl halide,which is subsequently treated with an alcohol of general formula:R′″₅—OH  (12)in which R′″₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group or agroup (b) in which R′₅ represents a piperidinyl group optionallyN-substituted with a C₁–C₄ alkyl group or R′₅ represents a group (d)comprising no carboxylic or alkali metal carboxylate group, and then, ifnecessary, the compound formed is deprotected, which gives the desiredcompounds of formula (1) in the hydrohalide form or in the free baseform when the compound of formula (10) is in excess, which hydrohalidecan be treated, if necessary, with a basic agent, such as an alkalimetal hydroxide or an alkali metal carbonate, to produce the desiredcompounds in the free base form.

G.—When R represents a group (e) in which R₁₀ represents a group (f)comprising no carboxylic or alkali metal carboxylate group, a compoundof formula (10), after protection of the amine functional group when Am′represents a group (Am₁) in which R₂ represents hydrogen, is reacted,preferably in a halogenated hydrocarbon and generally at the refluxtemperature, with a halogenating agent, such as thionyl chloride, toproduce an acyl chloride, which is subsequently treated, preferably atambient temperature, with a compound of formula:

in which R″₅ has the same meaning as above, and then, if necessary, thecompound formed is deprotected, which gives, in the free base form, thedesired compounds of formula (1) in which R₁₀ represents a group (f) inwhich the R₁₁ group represents a group (a) in which R₅ represents aC₁–C₄ alkyl or C₃–C₆ cycloalkyl group.

H.—When R represents a group (e) in which R₁₀ represents a C₁–C₄ alkylgroup, an amino group or a group (c), a compound of formula (10), afterprotection of the amine functional group when Am′ represents a group(Am₁) in which R₂ represents hydrogen, is reacted, preferably in ahalogenated hydrocarbon and generally at the reflux temperature, with ahalogenating agent, such as thionyl chloride, to produce an acyl halide,which is subsequently treated, preferably at ambient temperature, withan amine of general formula:R′₁₀—NH₂  (14)or

in which R₆, R₇ and R₈ have the same meaning as above and R′₁₀represents a C₁–C₄ alkyl or amino radical, and then, if necessary, thecompound formed is deprotected, which gives, optionally after basictreatment, the desired compound of formula (1) in the hydrohalide formor in the free base form when the compound of formula (10) is in excess,which hydrohalide can be treated, if necessary, with a basic agent, suchas an alkali metal hydroxide or an alkali metal carbonate, to producethe desired compounds in the free base form.

I.—When R represents a group (e) in which R₁₀ represents a group (g)comprising no carboxylic or alkali metal carboxylate group, a compoundof formula (10), after protection of the amine functional group when Am′represents a group (Am₁) in which R₂ represents hydrogen, is reacted,preferably in a polar or apolar solvent, such as N,N-dimethylformamideor a halogenated hydrocarbon, for example dichloromethane, with a saltof a compound of general formula:

in which R₁₂ has the same meaning as above and R′₁₁ represents a C₁–C₄alkyl or C₃–C₆ cycloalkyl radical, the reaction taking place in thepresence of an acid scavenger such as an amine, for exampletriethylamine, and then, if necessary, the compound formed isdeprotected, which gives, in the free base form, the desired compoundsof formula (1) in which R₁₀ represents a group (g) in which the groupR₁₁ represents a group (a) in which R₅ represents a C₁–C₄ alkyl or aC₃–C₆ cycloalkyl group.

J.—When R represents a group (h), by reacting a compound of formula(10), after protection of the amine functional group when Am′ representsa group (Am₁) in which R₂ represents hydrogen, preferably in ahalogenated hydrocarbon and generally at the reflux temperature of themedium, with a halogenating agent, such as thionyl chloride, to producean acyl halide, which is subsequently treated with an amine of generalformula:

in which R₁₃ and R₁₄ have the same meaning as above, and then, ifnecessary, the compound formed is deprotected, which gives a salt of thedesired compound of formula (1), which is treated with a suitable basicagent, such as an alkali metal carbonate, to produce, in the free baseform, the desired compounds of formula (1).

K.—When R represents a group (e) in which R₁₀ represents the hydroxylgroup, a compound of formula (10), after protection of the aminefunctional group when Am′ represents a group (Am₁) in which R₂represents hydrogen, is reacted with a benzyloxyamine salt, for examplethe hydrochloride, in the presence of an acid scavenger, for example anamine such as triethylamine, and ofbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate,hereinafter referred to as BOP, and then, if necessary, the compoundformed is deprotected, which gives benzyloxyaminocarbonyl derivatives,which are hydrogenated in the presence of a suitable catalyst, forexample palladium charcoal or platinum black, to produce, in the freebase form, the desired compounds of formula (1).

In the processes E. to K. above, the protection of the amine functionalgroup of the compound of formula (10), i.e. the protection envisagedwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, canbe obtained, for example, by treatment by means of a compound whichmakes possible the attachment of a group which can be easily removed, inparticular by means of 9-fluorenylmethyl chloroformate, and thedeprotection is subsequently carried out by treatment with a secondaryamine, for example piperidine or diethylamine, in a suitable solvent,for example N,N-dimethylformamide.

Other compounds of formula (1) can be used as synthetic intermediatesfor compounds of the invention, in particular the cyano derivativeswhich also correspond to the general formula:

in which Am′, A, B, R′₁, T, W, W′, X and Z have the same meaning asabove.

Thus, the following methods, starting with the compounds of formula (18)in question, can be employed to prepare the compounds of formula (1) inwhich Y represents —CO—, Am represents a group (Am₁) or (Am₂), thisgroup comprising no carboxylic or alkali metal carboxylate group, orelse a group (Am₃) in which R₁₆ and/or R₁₇ and/or R₁₈ are different froman amino group or a C₁–C₄ alkylsulfonamido group, and in which R₁comprises no carboxylic or alkali metal carboxylate group, that is tosay:

L.—When R represents a group (e) in which R₁₀ represents hydrogen, acompound of formula (18) is hydrolyzed in the presence of a strong acid,such as, for example, sulfuric acid, and generally at ambienttemperature, which gives, in the free base form, the desired compoundsof formula (1).

M.—When R represents the group (I), a compound of formula (18) isreacted, preferably in an aprotic solvent, such as an aromatichydrocarbon, for example benzene or toluene, and usually at the refluxtemperature of the medium, with tributylazidotin, which gives, in thefree base form, the desired compounds of formula (1).

-   II. The compounds of formula (1) in which:    -   Y represents the —CO— group    -   R₁ comprises no carboxylic or alkali metal carboxylate group    -   Am represents a group (Am₁) comprising no carboxylic or alkali        metal carboxylate group and in which R₁₆ and/or R₁₇ and/or R₁₈        represent the amino group or a C₁–C₄ alkylsulfonamido group, or        else Am represents a group (Am₃) in which R₁₆ and/or R₁₇ and/or        R₁₈ represent the amino group or a C₁–C₄ alkylsulfonamido group,        can be obtained in the following way:    -   a) when R₁₆ and/or R₁₇ and/or R₁₈ represent the amino group, by        hydrogenating, preferably at ambient temperature and at normal        pressure, a nitro compound of formula:

-   -    in which A, B, R′₁, T, W, W′, X and Z have the same meaning as        above, R has the same meaning as above but comprises no        carboxylic or alkali metal carboxylate group, and Am′₁        represents either a group (Am₁) comprising no carboxylic or        alkali metal carboxylate group and in which R₁₆ and/or R₁₇        and/or R₁₈ represent the nitro group, or a group (Am₃), in which        R₁₆ and/or R₁₇ and/or R₁₈ represent the nitro group, in the        presence of a suitable catalyst such as Raney nickel, platinum        oxide or palladium oxide or zinc in hydrochloric acid medium,        and preferably in a polar solvent, for example an alcohol, which        gives, in the free base form, the desired compounds of formula        (1).    -   b) When R₁₆ and/or R₁₇ and/or R₁₈ represents a C₁–C₄        alkylsulfonamido group, by reacting an amino compound of        formula:

-   -    in which A, B, R′₁, T, W, W′, X and Z have the same meaning as        above, R has the same meaning as above but comprises no        carboxylic or alkali metal carboxylate group, and Am′₂        represents either a group (Am₁) comprising no carboxylic or        alkali metal carboxylate group and in which R₁₆ and/or R₁₇        and/or R₁₈ represent the amino group, or a group (Am₃) in which        R₁₆ and/or R₁₇ and/or R₁₈ represent the amino group, with a        halide of general formula:        Hal-SO₂—R′₁₆  (21)    -    or an anhydride of general formula:        (R′₁₆SO₂)₂O  (22)    -    in which R′₁₆ represents a linear or branched C₁–C₄ alkyl        radical, the reaction preferably taking place at ambient        temperature and in an organic solvent, for example an aprotic        solvent, and optionally in the presence of an acid acceptor,        such as an amine, for example triethylamine, which gives, in the        free base form, the desired compounds of formula (1).

-   III. The compounds of formula (1) in which:    -   Y represents the —CO— group    -   the combination formed by R, R₁ and Am, more precisely R, R₁,        and (Am₁) or (Am₂), comprising 1 or 2 carboxylic or alkali metal        carboxylate groups, that is to say 1 or 2 groups (a) above in        which R₅ represents hydrogen or an alkali metal atom,    -   can be obtained:    -   a) when, in this formula (1), one or two of the groups R, R₁,        and (Am₁) or (Am₂) comprise a —CO₂R₅ group in which R₅        represents hydrogen or an alkali metal atom, the other group(s)        being different from a —CO₂R₅ group in which R₅ represents a        C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, by saponifying, in the        presence of a basic agent, namely an alkali metal hydroxide, for        example sodium hydroxide, a compound of formula:

-   -    in which A, B, R, R₁, T, W, W′, X and Z have the same meaning        as above, Am′₃ represents a group (Am₁) or (Am₂) as defined        above and R, R₁, and (Am₁) or (Am₂) are such that one or two of        them comprise a —CO₂R″₅ group in which R″₅ has the same meaning        as above, the other group(s) being different from a —CO₂R₅ group        in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl        radical, which gives, in the free base form, the compounds of        formula (1) in which one or two of the groups R, R₁, and (Am₁)        or (Am₂) comprise a —CO₂R₅ group in which R₅ represents an        alkali metal atom, which compound is treated, if necessary, with        a strong acid, for example hydrochloric acid, which gives, in        the free base form, the desired compounds of formula (1) in        which R₅ represents hydrogen. However, when, in this formula        (1), R represents the cyano group and one of the groups R₁,        (Am₁) or (Am₂) comprises a carboxylic group, it is also possible        to treat, by means of tributyltin oxide, a compound of        formula (1) in which Y represents —CO—, A, B, T, W, W′, X and Z        have the same meaning as above, R represents the cyano group,        and R₁, (Am₁) and (Am₂) are such that one of them comprises a        —CO₂R″₅ group in which R″₅ has the same meaning as above, to        produce, in the free base form, the desired compounds of formula        (1).    -   b) When, in this formula (1), one of two of the groups R, R₁,        (Am₁) or (Am₂) comprises a —CO₂R₅ group in which R₅ represents        hydrogen or an alkali metal atom, and the other comprises a        —CO₂R₅ group in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆        cycloalkyl group, the third group being different from a —CO₂R₅        group in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl        radical,        -   either by hydrogenating a compound of formula:

-   -   -    in which A, B, R, R₁, T, W, W′, X and Z have the same            meaning as above, Am′₄ represents a group (Am₁) or (Am₂) as            defined above, and R, R₁, and (Am₁) or (Am₂) are such that            one of them comprises a —CO₂R″₅ group in which R″₅ has the            same meaning as above and another of them comprises a            benzyloxycarbonyl group, the third group being different            from a —CO₂R₅ group in which R₅ represents a C₁–C₁₀ alkyl or            C₃–C₆ cycloalkyl radical, in the presence of a suitable            catalyst, for example palladium charcoal or platinum black,            and preferably in an organic solvent;        -   or by hydrolyzing a compound of formula:

-   -   -    in which A, B, R, R₁, T, W, W′, X and Z have the same            meaning as above, Am′₅ represents a group (Am₁) or (Am₂) as            defined above, and R, R₁, and (Am₁) or (Am₂) are such that            one of them comprises a —CO₂R″₅ group in which R″₅ has the            same meaning as above and another of them comprises a            t-butoxy-carbonyl group, the third group being different            from a —CO₂R₅ group in which R₅ represents a C₁–C₁₀ alkyl or            C₃–C₆ cycloalkyl radical, in the presence of trifluoroacetic            acid, and preferably in an organic solvent, for example an            aprotic solvent such as methylene chloride,        -   which makes it possible to produce the desired compounds of            formula (1) in which one of two of the groups R, R₁, and            (Am₁) or (Am₂) comprises a —CO₂R₅ group in which R₅            represents a C₁–C₁₀alkyl or C₃–C₆ cycloalkyl group, and the            other comprises a —CO₂R₅ group in which R₅ represents            hydrogen, that is to say a carboxylic group, which compounds            can be treated, if necessary, with a suitable basic agent,            for example an alkali metal hydroxide, to produce, in the            free base form, the desired compounds of formula (1) in            which one of two of the groups R, R₁, and (Am₁) or (Am₂)            comprises a —CO₂R₅ group in which R₅ represents an alkali            metal atom, the other a group of formula —CO₂R₅ in which R₅            represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, which            compounds can themselves be treated, if necessary, with a            strong acid, for example hydrochloric acid, to produce, in            the free base form, the desired compounds of formula (1) in            which one of two of the groups R, R₁, and (Am₁) or (Am₂)            comprises a carboxylic group, the other a —CO₂R₅ group in            which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl            group.

-   IV. The compounds of formula (1) in which Y represents a group

-    can be obtained:    -   a) when R₂₂ represents hydrogen, by reducing a compound of        formula (1) in which Y represents the —CO— group, by means of an        alkali metal borohydride, such as sodium borohydride, and        preferably in a solvent such as an alcohol or an ether, which        gives, in the free base form, the desired compounds of formula        (1),    -   b) when R₂₂ represents a C₁–C₄ alkyl radical or an acyl radical        of formula —CO—R₂₃, by reacting the secondary alcohol thus        formed, that is to say a compound of formula (1) in which Y        represents the —CHOH— group, with:        -   either an alkali metal hydroxide, and then with a halide of            general formula:            R₂₃-Hal  (26)        -    in which Hal and R₂₃ have the same meaning as above,-   or an acyl halide of general formula:

-   -   -    in which Hal and R₂₃ have the same meaning as above, the            reaction taking place in the presence of an acid acceptor            such as pyridine,

    -   so as to produce, in the free base form, the desired compounds        of formula (1).

-   Depending on the structure of the starting product, mixtures of    compounds can be obtained during the reduction. These compounds can    be separated from their mixture according to conventional    techniques, for example by elution chromatography.

-   V. The compounds of formula (1) in which Y represents the —CH₂—    group can be prepared, preferably, by reducing a compound of    formula (1) in which Y represents the —CHOH— group, by means of an    alkali metal borohydride, such as sodium borohydride, in the    presence of trifluoroacetic acid, and preferably in a solvent such    as an alcohol, an ether or a halogenated hydrocarbon, which gives,    in the free base form, the desired compounds of formula (1).

Generally, the reduction of the compounds of formula (1) in which Yrepresents a —CO— or —CHOH— group is carried out at a temperature of theorder of −10° to +10° C., preferably at 0° C.

The compounds of formula (1) obtained in the free base form according toone or other of the methods described above can subsequently beconverted to pharmaceutically acceptable salts by reaction with asuitable organic or inorganic acid, for example oxalic, maleic, fumaric,methanesulfonic, benzoic, ascorbic, pamoic, succinic, hexamic,bismethylenesalicylic, ethanedisulfonic, acetic, propionic, tartaric,salicylic, citric, gluconic, lactic, malic, cinnamic, mandelic,citraconic, aspartic, palmitic, stearic, itaconic, glycolic,p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic ortheophyllineacetic acid, or with lysine or histidine.

The compounds of formula (2) in which R′ represents a cyano or —CO₂R″₅group, and also the compounds of formula (4) in which R″ represents acyano or —CO₂R″₅ group, can be prepared starting from a compound ofgeneral formula:

in which R′ represents a cyano or —CO₂R″₅ group and R′₁, T and X havethe same meaning as above, which compound is treated with a compound ofgeneral formula:

in which W, W′, Z and Hal have the same meaning as above and R₂₅represents a methoxy, acetylthio or nitro group or -A-B-Hal in which A,B and Hal have the same meaning as above, in the presence of a Lewisacid as catalyst, for example ferric chloride, stannic chloride oraluminum chloride, and in a solvent such as a halogenated hydrocarbon,so as to obtain a ketone of general formula:

in which R′ represents a cyano or —CO₂R″₅ group and R′₁, T, W, W′, X, Zand R₂₅ have the same meaning as above, which gives:

-   when R₂₅ represents an -A-B-Hal group, desired compounds of formula    (4),-   when R₂₅ represents the methoxy group, compounds which are    O-demethylated in the presence of a suitable agent, such as pyridine    hydrochloride, boron tribromide or aluminum chloride, to produce the    compounds of the formula (2) in which A′ represents OH,-   when R₂₅ represents the acetylthio group, compounds which are    treated by means of a suitable basic agent, such as an alkali metal    hydroxide, to produce the desired compounds of formula (2) in which    A represents SH,-   when R₂₅ represents the nitro group, compounds which are reduced by    hydrogenation in the presence of a suitable catalyst, such as    palladium charcoal, to produce the desired compounds of formula (2)    in which A′ represents NH₂.

Alternatively, the compounds of formula (2) in which A′ represents thehydroxyl group and R′ represents a cyano or —CO₂R″₅ group can beobtained starting from a compound of formula (28) which is treated withphosgene and then with a compound of general formula:

in which W, W′ and Z have the same meaning as above, the reaction takingplace in the presence of a Lewis acid, such as, for example, aluminumchloride or stannic chloride, to produce the ketones of formula (30) inwhich R₂₅ represents the methoxy group.

These ketones of formula (30) thus produced are then subjected toO-demethylation in the presence of a suitable agent, such as pyridinehydrochloride, boron tribromide or aluminum chloride, to finally producethe desired compounds.

The compounds of formula (2) in which A′ represents the hydroxyl groupand R′ represents the hydroxymethyl group can be prepared starting froma compound of formula (2) in which R′ represents a —CO₂R′₅ group,according to the sequence of stages below:

a) the ester of formula (2) in question is treated, at the refluxtemperature of the medium, by means of glycol in the presence ofp-toluenesulfonic acid, to form a diether of general formula:

in which R′₁, R″₅, T, X, W, W′ and Z have the same meaning as above,

b) this compound of formula (32) is reduced by means of an alkali metalhydride such as lithium aluminum hydride, and in a solvent such as anether, to produce a dialcohol of general formula:

in which R′₁, T, X, W, W′ and Z have the same meaning as above,

c) the dialcohol thus obtained is deprotected by means of pyridinep-toluenesulfonate, preferably at the reflux temperature of the medium,which gives the desired compounds.

The compounds of formula (2) in which R′ represents the group (k) can beobtained by treating a compound of formula (2) in which R′ represents a—CO₂R″₅ group, with acetamide oxime in the presence of an alkali metalhydride, which gives the desired compounds.

The compounds of formula (4) in which R″ represents the cyano group, a—CO₂R″₅ group or the group (k) can be prepared by reacting, preferablyat the reflux temperature, a compound of formula (2) in which R′represents a cyano or —CO₂R″₅ group, with a dihalogenated compound ofgeneral formula:Hal-B-Hal  (34)in which Hal represents a halogen atom, preferably bromine, and B hasthe same meaning as above, the reaction taking place in the presence ofa basic agent, such as an alkali metal hydroxyl or carbonate, to givethe desired compounds.

Likewise, the compounds of formula (4) in which R″ represents anR₄—O—N═CH— group can be obtained:

a) by reducing an ester of formula (28) in which R′ represents a group(a) in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical,by means of a suitable agent, such as a hydride, for example lithiumaluminum hydride, to form an alcohol of general formula:

in which R′₁, T and X have the same meaning as above,

b) by oxidizing this alcohol of formula (35) with oxalyl chloride so asto form the aldehyde of general formula:

in which R′₁, T and X have the same meaning as above, and

c) by reacting the aldehyde thus obtained, with a compound of generalformula:R₄—O—NH₂  (37)optionally in the form of one of its salts, in an acid-scavengingsolvent, for example pyridine, to form the oxime of general formula:

in which R′₁, T and R₄ have the same meaning as above.

The compound of formula (38) in question is then treated either with acompound of formula (29) so as to produce the desired compounds, orfirst with phosgene, and then with a compound of formula (31), andfinally with an agent suitable for causing an O-demethylation, forexample aluminum chloride, pyridine hydrochloride or boron tribromide,which gives the desired compounds.

As regards the compounds of formula (6), they can be obtained asfollows:

A—The compounds of formula (6) in which R″ represents a —CO₂R″₅ grouplocated at position 5 and R′₁, located at position 2, represents a C₁–C₆alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl group, can be preparedaccording to the sequence of stages below:

a) first, a benzoate of general formula:

in which R″₅, T and X have the same meaning as above, is treated withmethanesulfonic acid in the presence of phosphorus pentoxide and ofhexamethylenetetramine, to give a formyl derivative of general formula:

-   -   in which R″₅, T and X have the same meaning as above,

b) this compound of formula (40) is subsequently reacted with an esterof general formula:

in which R″₁, represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl orbenzyl group, which gives the compounds of general formula:

in which R″₁, R″₅, T and X have the same meaning as above,

c) this ester of formula (42) is treated with formic acid ortrifluoroacetic acid, which gives the acids of general formula:

in which R″₁, R″₅, T and X have the same meaning as above,

d) this compound is cyclized in the presence of benzenesulfonyl or ofp-toluenesulfonyl chloride and of an acid acceptor, such astriethylamine, which gives the desired compounds of formula (6).

B—The compounds of formula (6) in which R″ represents the cyano grouplocated at position 5, and R′₁, located at position 2, represents aC₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl group, can be preparedas follows:

a) first a formyl derivative of general formula:

in which Hal, T and X have the same meaning as above, is treated withzinc cyanide in the presence of a suitable catalyst, for example apalladium derivative, such as tetrakis(triphenylphosphine)palladium,which gives the compounds of general formula:

in which T and X have the same meaning as above,

b) this compound of formula (45) is subsequently demethylated withlithium chloride, which gives the compound of general formula:

in which T and X have the same meaning as above,

c) this compound of formula (46) is then treated with an ester ofgeneral formula:

in which R″₁, and R″₅ have the same meaning as above, in the presence ofa basic agent, such as an alkali metal carbonate, which gives thecompounds of general formula:

in which R″₁, R″₅ T and X have the same meaning as above,

d) and e) this ester of formula (48) is saponified in the presence of abasic agent, such as an alkali metal hydroxide, and the acid thusobtained is cyclized in the presence of benzenesulfonyl orp-toluenesulfonyl chloride and of an acid acceptor, such astriethylamine, which gives the desired compounds.

C—The compounds of formula (6) in which R″ represents a cyano or —CO₂R″₅group located at position 5, and R′₁, located at position 2, representsa group (m) in which R₁₁ represents a —CO₂R″₅ group, can be obtainedaccording to the sequence of stages below:

a) either, a cyano derivative of general formula:

in which T and X have the same meaning as above is treated with iodinein the presence of aqueous ammonia, to form an iodo derivative ofgeneral formula:

in which T and X have the same meaning as above, or, a compound ofgeneral formula:

in which T and X have the same meaning as above, is first treated withan alkali metal iodide and an oxidizing agent, such as an alkali metalhypochlorite, for example sodium hypochlorite, then with a halogenatingagent, such as thionyl chloride, and finally with an alcohol of generalformula:R″₅—OH  (52)in which R″₅ has the same meaning as above, which gives an iododerivative of general formula:

in which R″₅, T and X have the same meaning as above,

b) the iodinated derivative of formula (50) or (53) is reacted with anacetylenic ester of general formula:HC≡C—(CH₂)_(p)—CO₂R″₅  (54)in which R″₅ and p have the same meaning as above, in the presence of asuitable catalyst, such as a palladium derivative, for exampledichlorobis(triphenylphosphine)palladium, and of cuprous iodide, and inthe presence of tetramethylguanidine, which gives the desired compoundsof formula (6).

D—Alternatively, the compounds of formula (6) in which R″ represents acyano or —CO₂R″₅ group located at position 5, and R′₁, located atposition 2, represents a C₃–C₆ alkyl group, can be prepared by reactingan iodinated derivative of formula (53) with an acetylenic derivative ofgeneral formula:

in which p has the same meaning as above, and in the presence of asuitable catalyst, such as a palladium derivative, for exampletetrakis(triphenylphosphine)-palladium, and of cuprous iodide, whichgives the desired compounds of formula (6).

E—The compounds of formula (6) in which R″ represents a cyano or —CO₂R″₅group located at position 6, and R′₁, located at position 2, has thesame meaning as above, can be obtained as follows:

a) a compound of general formula:

in which R₂₆, T and X have the same meaning as above is reacted withtrifluoromethanesulfonic acid anhydride, in the presence of pyridine, toproduce a compound of general formula:

in which R₂₆, T and X have the same meaning as above,

b) the compound thus formed is reacted with an acetylenic derivative ofgeneral formula:HC≡C—R′₁  (58)in which R′₁ has the same meaning as above, in the presence of asuitable catalyst, for example a palladium derivative, such asdichlorobis(triphenyl-phosphine)palladium, and of an acid acceptor, suchas triethylamine, to form the compounds of general formula:

in which R′₁, R₂₆, T and X have the same meaning as above,

c) this compound of formula (59) is then cyclized in the presence ofboron tribromide at a temperature of less than −50° C., which gives theheterocyclic compounds of general formula:

in which R′₁, T and X have the same meaning as above and R′₂₆ representsthe cyano group, which gives desired compounds of formula (6), or R′₂₆represents a carboxylic group, which gives an acid,

d) this acid is esterified with an alcohol of formula (52), which givesdesired compounds of formula (6).

F—The compounds of formula (6) in which R″ represents a cyano or —CO₂R″₅group located at position 4, and R′₁, located at position 2, has thesame meaning as above, can be obtained as follows:

a) a compound of general formula:

in which R₂₆, T and X have the same meaning as above, is reacted withtrifluoromethanesulfonic anhydride, in the presence of pyridine, toproduce a compound of general formula:

in which R₂₆, T and X have the same meaning as above,

b) the compound thus formed is reacted with an acetylenic derivative offormula (58), in the presence of a suitable catalyst, such as apalladium derivative, for exampledichlorobis(triphenylphosphine)palladium, and of an acid acceptor, suchas triethylamine, to form the compounds of general formula:

in which R′₁, R₂₆, T and X have the same meaning as above,

c) this compound of formula (63) is then cyclized in the presence ofboron tribromide, which gives the heterocyclic compounds of generalformula:

in which R′₁, T and X have the same meaning as above and R′₂₆ representsthe cyano group, which gives the desired compounds of formula (6), orR′₂₆ represents a carboxylic group, which gives an acid,

d) this acid is esterified with an alcohol of formula (52), which givesdesired compounds of formula (6).

G—The compounds of formula (6) in which R″ represents a cyano or —CO₂R″₅group located at position 7, and R′₁, located at position 2, has thesame meaning as above, can be obtained as follows:

a) an alcohol of general formula:

in which R₂₇ represents a cyano or formyl group and T and X have thesame meaning as above, is treated with methyl iodide, in the presence ofan alkali metal hydride, to give a compound of general formula:

in which R₂₇, T and X have the same meaning as above,

b) the compound thus formed is reacted with trifluoromethanesulfonicanhydride, to give a compound of general formula:

in which R₂₇, T and X have the same meaning as above,

c) the compound thus formed is treated with a compound of formula (58),in the presence of a suitable catalyst, such as a palladium derivative,for example dichlorobis(triphenylphosphine)palladium, which produces acompound of general formula:

in which R′₁, R₂₇, T and X have the same meaning as above,

d) the compound of formula (68) thus formed is subsequently reacted:

-   when R₂₇ represents the cyano group, with lithium chloride, to form    the desired compounds of formula (6) in which R″ represents the    cyano group,-   when R₂₇ represents the formyl group, with an alkali metal cyanide    in the presence of manganous oxide and acetic acid, to give a    compound of general formula:

-    in which R₂₇, T and X have the same meaning as above, which is    cyclized with lithium chloride, to give a mixture of ester and of    acid of general formula:

-    in which R₂₈ represents the methoxycarbonyl or carboxylic group and    R′₁, T and X have the same meaning as above, which mixture is    treated with methanol in the presence of a strong acid, such as    sulfuric acid, which gives desired compounds of formula (6) in which    R″ represents the methoxycarbonyl group.-    The other compounds of formula (6), that is to say the compounds of    formula (6) in which R″, located at position 7, represents a —CO₂R″₅    group, with the exception of the methoxycarbonyl group, can be    obtained by saponifying an ester of formula (6) in which R″, located    at position 7, represents the methoxycarbonyl group, in the presence    of a basic agent, such as an alkali metal hydroxide, to give a salt,    which is acidified with a strong acid, such as hydrochloric acid, to    give a 7-carboxybenzofuran derivative, which is esterified with an    alcohol of general formula:    R′_(a)—OH  (71)-    in which R′_(a) represents a C₂–C₁₀ alkyl or C₃–C₆ cycloalkyl    radical, which gives desired compounds of formula (6).

H—The compounds of formula (6) in which R″ represents the group (k) canbe obtained by cyclizing a compound of formula (6) in which R″represents a —CO₂R″₅ group, by means of acetamide oxime, in the presenceof an alkali metal hydride, such as sodium hydride, which gives thedesired compounds.

I—The compounds of formula (6) in which R″ represents an R₄—O—N≡CH—group in fact correspond to the compounds of formula (38), thepreparation of which was described above.

Most of the other starting compounds or intermediate compounds involvedin the various processes described above are known compounds orcompounds which can be prepared by known methods.

For example, some of the amines of formula (3) or formula (5) are knownand described in particular in U.S. Pat. No. 4,831,054 or EP 471609, orcan be prepared by the methods described therein.

For example, 1-(2-chloroethyl)-4-dicyclohexylmethylpiperazine can beprepared by reacting N-dicyclohexylmethylpiperazine with ethylene oxide,to form 1-(2-hydroxyethyl)-4-dicyclohexylmethylpiperazine, which issubsequently treated with a chlorinating agent, such as thionylchloride, to produce the desired compound.

Likewise, 1-(2-chloroethyl)-3,5-diethylpiperidine can be produced by asimilar process involving the formation of1-(2-hydroxyethyl)-3,5-diethylpiperidine from ethylene oxide and2,5-diethylpiperidine, and then the conversion thereof using ahalogenating agent, such as thionyl chloride, to produce the desiredcompound.

Benzofuran or benzothiophene derivatives which comprise amonoalkylamino- or dialkylaminoalkoxybenzoyl chain and which aresubstituted on the homocycle with an amino group, which itself may ormay not be substituted, are already known. Such compounds, which havebeen disclosed in patent EP 0471609, have been shown to possessadvantageous antiarrhythmia properties resulting in particular inpharmacological effects of Vaughan-Williams classes 1, 2, 3 and 4.

However, these benzofuran and benzothiophene derivatives exhibit lowsolubility in aqueous medium and low availability when administeredorally.

In point of fact, it has now been discovered, in the context of theinvention, that benzofuran or benzothiphene derivatives comprising anaminoalkoxybenzoyl chain and other groups attached to the heterocyclevia a carbon atom exhibit a pharmacological profile similar to that ofthe prior compounds, while at the same time offering better metabolicstability, higher solubility and greater bioavailability whenadministered orally.

The results of pharmacological tests carried out for the purpose ofdetermining the properties of the compounds of the invention withrespect to the cardiovascular system are listed below.

I. Antiarrhythmic Activity

The aim of this test is to determine the ability of the compounds of theinvention to provide protection against reperfusion-induced arrhythmias.To this end, use was made of the method reported by A. S. Manning et al.in Circ. Res. 1984, 55: 545–548 modified as follows:

-   -   Rats, divided into batches, are first anesthetized with sodium        pentobarbital (60 mg/kg intraperitoneally), and are then        intubated and maintained under assisted respiration.

A cannula for intravenous administration is subsequently inserted intotheir right jugular vein, an intravenous dose of the compound to bestudied is administered and, 5 minutes later, a ligature loop is placedaround the left anterior descending coronary artery in the immediateproximity of its origin. This artery is then occluded for 5 minutes bypulling on the ends of the ligature, so as to induce reperfusion byrelaxing the tension.

The arrhythmias induced by this reperfusion are then evaluated.

A similar test is carried out with oral administration. In this case,the compound to be studied is administered 120 minutes before ligatingthe left anterior descending coronary artery.

The results of these tests showed that the compounds of the inventionprotect the treated animals in a significant manner, ranging up to 100%at doses of between 0.3 and 10 mg/kg intraveously and 10 to 90 mg/kgorally.

II. Antiadrenergic Properties

The aim of this test is to determine the ability of the compounds of theinvention to reduce the increase in blood pressure induced byphenylephrine (anti-α effect) and the acceleration in heart rate inducedby isoprenaline (anti-β effect) in dogs anesthetized beforehand withpentobarbital and chloralose.

For each dog, the dose of phenylephrine (5 or 10 μg/kg) which leads toan increase in arterial pressure of between 25 and 40 mm Hg and the doseof isoprenaline (0.9 or 1 μg/kg) which should lead to an increase inheart rate of between 60 and 120 beats/minute are first determined.

The doses of phenylephrine and of isoprenaline thus determined areinjected alternately every 10 minutes and, after obtaining 2 successivereference responses, a dose of the compound to be studied isadministered intravenously.

Anti-α Effect

The percentage reduction, by the compound of the invention, of theinduced hypertension, compared to the reference hypertension obtainedbefore injection of this compound (approximately 100 mm Hg), isrecorded.

Anti-β Effect

The percentage reduction, by the compound to be studied, of the inducedacceleration in heart rate is recorded.

The results of these tests show that, at doses varying from 1 to 10mg/kg, the compounds of the invention exhibit anti-α and/or anti-βeffects which result in reductions, ranging from 50% to virtually 100%,in the induced hypertension and/or in the induced increase in heartrate.

III. Atrial Fibrillation

The aim of this test is to evaluate the effectiveness of the compoundsof the invention with respect to atrial fibrillation induced bypermanent stimulation of the vagus nerve in dogs anesthetized accordingto the method described in Circulation 1993; 88: 1030–1044.

The compounds to be studied are administered at the cumulative doses of3 and 10 mg/kg in slow intravenous infusions of 10 minutes during anepisode of sustained atrial fibrillation.

At the dose of 10 mg/kg, the compounds of the invention generallyconvert 100% of the atrial fibrillations into a sinus rhythm and preventthe reinduction thereof in 50 to 100% of cases. At this dose,significant increases in the heart period and in the atrial effectiverefractory periods for various basal values of the heart period areobserved.

IV. Inhibitory Effects on the Neurohormonal System

The aim of this test is to search for inhibitory effects of thecompounds of the invention with respect to vasoconstrictive effectsinduced by various peptides such as noradrenaline (NA), angiotensin II(A-II), arginine vasopressin (AVP), neuropeptide Y (NPY) and endothelin(ET), and also with respect to tachycardic effects induced byisoprenalin (Iso), in conscious rats.

An arterial catheter (right carotid artery), for measuring the arterialpressure, and a venous catheter (right jugular vein), for injecting theproduct to be studied, are implanted, 24 hours before the test, in maleSprague Dawley rats weighing approximately 300 g. On the following day,the rats are placed in cylindrical cages and the arterial catheter isconnected to a pressure sensor via a revolving joint on a pendulum. Thispressure sensor is itself connected to a polygraph for recording thearterial pressure.

The action of the compounds of the invention, administeredintravenously, is then investigated with respect to vasoconstrictiveeffects induced by NA (1 μg/kg), A-II (100 μg/kg) and AVP (40 μg/kg) atthe respective doses of either 3, 10 and 30 mg/kg or 1.3 to 10 mg/kg,and solely at the dose of 10 mg/kg with respect to vasoconstrictiveeffects induced by NPY (6 μg/kg) and ET (0.5 μg/kg), or tachycardiceffects induced by Iso (1 μg/kg).

First, the various peptide agonists are solubilized in 0.9%physiological saline and the compound to be studied is solubilized in asuitable solvent. These peptides are subsequently injected as a bolus ina volume of 0.05 ml/kg, 30 and 10 minutes before intravenousadministration of 0.1 ml/kg of a solution of the compound to be studiedor of solvent. These peptide injections are subsequently repeated 10,30, 60 and 120 minutes after administration of the compound to bestudied. Depending on the duration of action of the compound to betested, these injections can optionally be repeated every 30 minuteswithout ever exceeding 5 hours in total.

The variations in arterial pressure after administration of a givenpeptide are then evaluated by measuring, at various times, thedifference between the maximum effect induced by the peptide angonistand the basal value of the arterial pressure. The results obtained showthat NA, A-II, AVP, NPY and ET induce respective increases in thearterial pressure of 45±3, 40±3, 30±2 and 34±4 mmHg, and Iso induces anincrease in the heart rate of 209±7 beats per minute.

In addition, it is observed that the compounds of the inventionantagonize in a dose-dependent manner the vasoconstrictive effectsinduced by NA, A-II and AVP. They also antagonize the effects induced byNPY and ET, and the increase in heart rate induced by Iso. At thehighest doses, the maximum inhibition obtained after 15 minutes rangesbetween 40 and 80% and the duration of action is at least greater thanor equal to 30 minutes.

V. Toxicity

The toxicity of the compounds of the invention has proved to becompatible with their therapeutic use.

The pharmaceutical compositions according to the invention can beprovided in any form suitable for administration in human or veterinarytherapy. For example, the pharmaceutical compositions of the presentinvention can be formulated for oral, sublingual, subcutaneous,intramuscular, intravenous, transdermal or rectal administration. Asregards the administration unit, this can take the form, for example, ofa tablet, a sugar-coated tablet, a capsule, a hard gelatin capsule, apowder, a suspension, a syrup or granules for oral administration, of asuppository for rectal administration or of a solution or suspension forparenteral administration.

The pharmaceutical compositions of the invention may comprise, peradministration unit, for example, from 50 to 500 mg by weight of activeingredient for oral administration, from 50 to 200 mg of activeingredient for rectal administration and from 50 to 150 mg of activeingredient for parenteral administration.

Depending on the route of administration chosen, the pharmaceutical orveterinary compositions of the invention will be prepared by combiningat least one of the compounds of formula (1), or a pharmaceuticallyacceptable salt of this compound, with a suitable excipient, the latterpossibly consisting, for example, of at least one ingredient selectedfrom the following substances: lactose, starches, talc, magnesiumstearate, polyvinylpyrrolidone, alginic acid, colloidal silica,distilled water, benzyl alcohol or sweetening agents.

When the compositions are tablets, these tablets can be treated suchthat they exhibit sustained or delayed activity and that theycontinually release a predetermined amount of active principle.

The following nonlimiting examples illustrate the preparation of thecompounds and compositions of the invention:

EXAMPLE 1 Methyl2-butyl-3-[4-[3-dibutylaminopropoxy]benzoyl]-1-benzofuran-5-carboxylateA. Methyl 3-formyl-4-hydroxybenzoate

2 g of phosphoric anhydride and 40 ml of methanesulfonic acid are placedin a three-necked round-bottomed flask. The mixture is heated toapproximately 85° C., the heating is then stopped and an intimatemixture of 7.6 g (0.05 mol) of methyl 4-hydroxybenzoate and of 10.22 g(0.073 mol) of hexamethylenetetramine is added in fractions, at atemperature of 85° C. to 90° C.

Once the addition has been completed, the mixture is heated at 85°/90°C. for 2 hours and allowed to cool to 70° C., and then 60 ml of waterare added. The mixture is allowed to gradually return to ambienttemperature, and then extracted with ethyl acetate. It is then washedwith water, an aqueous sodium bicarbonate solution, water, a potassiumacid sulfate solution, again with water to neutrality and, finally, witha saturated sodium chloride solution.

In this way, 6.73 g of desired compound are obtained in the crude form.

Yield: 75% M.p.: 80–81° C.

B. tert-Butyl 2-bromohexanoate

25.16 g (0.129 mol) of 2-bromohexanoic acid are dissolved in 200 ml ofbenzene containing 1 ml of N,N-dimethylformamide. The solution is cooledby means of a water/ice mixture and 32.8 g (2 equivalents) of oxalylchloride in 50 ml of benzene are added dropwise at a temperature ofapproximately 7° C. The mixture is stirred for 1 hour under coldconditions and then allowed to return to ambient temperature. Thesolvent is evaporated off. The acid chloride obtained is then dissolvedin 500 ml of dichloromethane, and is then added, at a temperature ofless than 10° C., to a mixture of 120 g (12.5 equivalents) oftert-butanol and of 24.9 g (1.75 equivalent) of triethylamine.

The mixture is allowed to return to ambient temperature and is washedwith 500 ml of water and then with 100 ml of 3% hydrochloric acid. Thedichloromethane is evaporated off and the residue is then taken up withdiethyl ether and washed with water, an aqueous sodium bicarbonatesolution, water, a potassium sulfate solution, water and, finally, witha saturated sodium chloride solution. Distillation is then carried outunder reduced pressure.

In this way, 25 g of desired compound is obtained.

Yield: 77% B.p.: 104–107° C. (20 mmHg)

C. tert-Butyl 2-[(2-formyl-4-methoxycarbonyl)phenoxy]hexanoate

6.73 g (37 mmol) of methyl 3-formyl-4-hydroxybenzoate and 10.32 g (1.1equivalent) of tert-butyl 2-bromohexanoate are dissolved in 100 ml ofN,N-dimethylformamide.

6.45 g (1.25 equivalent) of potassium carbonate are then added and themixture is heated in a water bath (approximately at 80° C.) for 3 hours.The N,N-dimethylformamide is then evaporated off. The residue is takenup with ethyl acetate and washed with a 3% solution of potassium acidsulfate, with water and with a saturated sodium chloride solution.Purification is carried out by chromatography on silica (eluent: 100/2dichloromethane/ethyl acetate).

In this way, 11.4 g of desired compound are obtained.

Yield: 88%

D. 2-[(2-Formyl-4-methoxycarbonyl)phenoxy]hexanoic acid

A mixture of 17.16 g of tert-butyl2-[(2-formyl-4-methoxycarbonyl)phenoxy]hexanoate and 100 ml of formicacid are stirred at ambient temperature for 24 hours. The mixture isthen diluted with water and extracted with ethyl acetate. Washing iscarried out with water until a neutral pH is obtained, and then with asaturated sodium chloride solution.

In this way, 14.7 g of desired compound are obtained.

Yield: 100%

E. Methyl 2-butyl-1-benzofuran-5-carboxylate

52.5 ml of benzenesulfonyl chloride dissolved in 250 ml of toluene areadded to a mixture of 141.6 ml of triethylamine in 250 ml of toluene.Heating is carried out at 80° C. and then 85.3 g of2-[(2-formyl-4-methoxycarbonyl)phenoxy]hexanoic acid dissolved in 500 mlof toluene are added, dropwise, at a temperature of less than or equalto 90° C.

Once the addition has been completed, the heating is continued for 0.5hour, and the mixture is allowed to return to ambient temperature and isdiluted with ethyl acetate. Washing is then carried out with water, apotassium acid sulfate solution, water, a sodium bicarbonate solution,water and a saturated sodium chloride solution. Distillation is thencarried out under reduced pressure.

In this way, 28.4 g of desired compound are obtained.

Yield: 39% relative to the methyl 4-hydroxybenzoate B.p.: 126–132° C.(0.03 mbar)

F. Methyl 2-butyl-3-(4-methoxybenzoyl)-1-benzofuran-5-carboxylate

Under argon, 45.6 g (0.28 mol) of ferric chloride are dissolved in 270ml of dichloroethane and then 32.51 g (0.14 mol) of methyl2-butyl-1-benzofuran-5-carboxylate dissolved in 180 ml of dichloroethaneare added at approximately 10° C. 48.2 g (0.28 mol) of anisoyl chloridedissolved in 180 ml of dichloroethane are subsequently added, at between10 and 15° C. The mixture is allowed to return to ambient temperatureand then stirred for 5 hours at this temperature. The reaction mixtureis poured onto an ice/water mixture and the precipitate is then filteredoff.

The filtrate is separated by settling, and the aqueous phase isextracted with dichloromethane. The organic phases are washed with asodium bicarbonate solution, water and a saturated sodium chloridesolution, and then purification is carried out by crystallization.

In this way, 48.84 g of desired compound are obtained.

Yield: 95% M.p.: 75–78° C.

G. Methyl 2-butyl-3-(4-hydroxybenzoyl)-1-benzofuran-5-carboxylate

48.84 g of methyl2-butyl-3-(4-methoxybenzoyl)-1-benzofuran-5-carboxylate and 55 g ofaluminum chloride are dissolved in 550 ml of toluene. Heating is carriedout at 60° C., in a water bath, for 2 hours and then toluene isseparated off by settling.

The residue is dissolved in tetrahydrofuran, ice is added and themixture is stirred for 2 hours. Separation is carried out by settlingand the aqueous phase is extracted with ethyl acetate. The 3 organicphases are pooled and washing is carried out with water and then with asaturated aqueous sodium chloride solution. Purification is then carriedout by crystallization from diisopropyl ether.

In this way, 26.45 g of desired compound are obtained.

Yield: 56% M.p.: 152–153° C.

H. Methyl2-butyl-3-[4-(3-dibutylamino)propoxy]-benzoyl]-1-benzofuran-5-carboxylate

2.14 g (6 mmol) of methyl2-butyl-3-(4-hydroxybenzoyl)-1-benzofuran-5-carboxylate, 1.25 g (6 mmol)of 3-chloro-1-(dibutylamino)propane and 1 g of potassium carbonate aredissolved in 35 ml of methyl ethyl ketone. The mixture is brought toreflux for 22 hours, dilution is performed with water and extraction iscarried out with ethyl acetate. Washing is carried out with a saturatedsodium chloride solution and purification is carried out bychromatography on silica (eluent: 5/5 hexane/ethyl acetate).

In this way, 2.95 g of desired compound are obtained in the free baseform.

Yield: 94%

Nuclear magnetic resonance (NMR) spectrum: standard

EXAMPLE 2 Methyl2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylateoxalate

1.957 g of methyl2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylateand 0.338 g (1 equivalent) of oxalic acid are dissolved in methanol.

Evaporation is carried out, the residue is taken up in diethyl ether,and trituration then evaporation are performed. Drying is subsequentlycarried out under vacuum.

In this way, 2.13 g of desired compound are obtained.

Yield: 93% M.p.: 82–84° C.

NMR spectrum: standard

The following compound was prepared by following the same process asabove (Example 1 and Example 2):

Methyl2-butyl-6-methyl-3-[4-[3-(1-piperidinyl)propoxy]benzoyl]-1-benzofuran-5-carboxylatehydrochloride (Example 3).

M.p.: 181–183° C. (diethyl ether) NMR spectrum: standard

EXAMPLE 4 Cyclohexyl2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylateoxalate

A mixture of 3.25 g of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylicacid and 3 ml of thionyl chloride in 60 ml of chloroform is brought toreflux for 1 hour. It is concentrated to dryness and then successiveoperations of taking up in diethyl ether and concentrating are carriedout, which gives an acyl chloride, which is subsequently used in crudeform. 50 ml of cyclohexanol are then added and heating is carried out at100° C. for 2 hours. After cooling, distillation is carried out undervacuum in order to remove the cyclohexanol. The nondissolved fraction ischromatographed on silica (eluent: chloromethane/methanol: 98/2) and themain fraction is taken up in a dilute aqueous solution of sodiumcarbonate. Extraction with diethyl ether, drying and concentrating arecarried out, which makes it possible to obtain the desired product inthe free base form, which is salified by adding oxalic acid in absoluteethanol.

In this way, 2.203 g of desired compound are recovered.

Yield: 50.6% M.p.: 96° C. NMR spectrum: standard

EXAMPLE 52-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-N-hydroxy-1-benzofuran-5-carboxamideoxalate A.2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-N-benzyloxy-1-benzofuran-5-carboxamide

2.45 g of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl-1-benzofuran-5-carboxylicacid, 0.855 g (1.1 equivalent) of benzyloxyamine hydrochloride, 2.36 g(1.1 equivalent) of BOP and 2 ml (approximately 3 equivalents) oftriethylamine are reacted in 70 ml of dichloromethane. The mixture isstirred for 1 hour at room temperature and evaporated, and the residueis taken up in ethyl acetate. The extracts are then washed with water, apotassium acid sulfate solution, water, a sodium bicarbonate solution,water until a neutral pH is obtained, and then with a saturated sodiumchloride solution.

In this way, approximately 3 g of crude desired compound are obtained.

B.2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-N-hydroxy-1-benzofuran-5-carboxamideoxalate

3.24 g of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-N-benzyloxy-1-benzofuran-5-carboxamidein 100 ml of methanol are hydrogenated in the presence of 5% palladiumcharcoal, at ambient temperature and at normal pressure. Filtration overdiatomaceous earth and evaporation are carried out. Purification is thencarried out by chromatography on silica (eluent: 90/10/0.5dichloromethane/methanol/aqueous ammonia), which gives 1.82 g (yield:66%) of the desired product in the base form.

1.565 g of the base thus obtained are subsequently introduced into asolution of 0.270 g of oxalic acid in methanol. Evaporation is carriedout, the residue is taken up with diethyl ether, and this is allowed tocrystallize.

In this way, the desired compound is obtained in the form of anamorphous powder.

NMR spectrum: standard

EXAMPLE 6 Methyl2-butyl-3-[4-[3-[(2,2-dimethylpropyl)amino]propoxy]benzoyl]-1-benzofuran-5-carboxylate

16.73 g of methyl2-butyl-3-[4-(3-bromopropoxy)benzoyl]-1-benzofuran-5-carboxylate, 15.52g (5 equivalents) of neopentylamine and 19.7 g of potassium carbonateare introduced into 200 ml of dimethyl sulfoxide.

The mixture is stirred at ambient temperature for 18 hours, evaporationis carried out, the residue is taken up in water, and extraction iscarried out with ethyl acetate. Washing is subsequently carried outtwice with water and then with a saturated sodium chloride solution.Purification is then carried out by chromatography on silica (eluent:95/5 dichloromethane/methanol) and crystallization from heptane isallowed to take place.

In this way, 10.6 g of desired compound are obtained.

Yield: 62.5% M.p.: 61–63° C. NMR spectrum: standard

EXAMPLE 72-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-N,N-diethyl-1-benzofuran-5-carboxamideoxalate

2.27 g of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylicacid and 2.5 ml of thionyl chloride are introduced into 50 ml ofchloroform.

The mixture is brought to reflux for 1 hour and evaporation is carriedout. The residue is taken up in diethyl ether and evaporation is carriedout twice. The residue is subsequently dissolved in 50 ml ofdichloromethane and 1.61 g of N,N-diethylamine dissolved in 10 ml ofdichloromethane are added.

Evaporation is carried out, the residue is taken up in a potassiumcarbonate solution and extraction is then carried out with diethylether. Washing is subsequently carried out with water and a saturatedsodium chloride solution and purification is carried out bychromatography on silica (eluent: 95/5 dichloromethane/methanol), whichgives 1.65 g (yield: 66%) of desired compound in the free base form.1.62 g of the base thus obtained and 0.259 g of oxalic acid aresubsequently dissolved in methanol, and then evaporation is carried out.The residue is taken up in diethyl ether and crystallization is allowedto take place. Filtration, washing with diethyl ether and drying undervacuum are carried out.

In this way, 1.54 g of desired compound are obtained in the form of asolid.

NMR spectrum: standard

EXAMPLE 8[2-(Dimethylamino)ethanol]2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylateoxalate

Under a nitrogen atmosphere, 1.93 g (3.8 mmol) of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylicacid and 0.615 g of carbonyldiimidazole are mixed in 20 ml ofN,N-dimethylformamide. The reaction medium is heated at 40° C. for 1hour, and then 0.583 g of 1,8-diazabicyclo-[5.4.0]undec-7-ene, followedby 0.678 g (7.60 mmol) of 2-(dimethylamino)ethanol, are added. Themixture is maintained at 40° C. for 18 hours and is then concentrated todryness. Extraction is subsequently carried out with ethyl acetate, theextract is washed with water and a saturated sodium chloride solutionand purification is carried out by chromatography on silica (eluent:90/10 dichloromethane/methanol), to produce 1.47 g of desired product inthe base form, which base is then treated with a solution of oxalic acidin absolute ethanol.

In this way, 1.122 g of desired compound are recovered in the form of anamorphous solid.

Yield: 66.8% NMR spectrum: standard

EXAMPLE 9 Methyl3-{[(2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl)carbonyl]amino}propanoate

2.54 g (5 mmol) of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylicacid, 0.768 g (5.5 mmol) of 2-(methoxycarbonyl)ethylamine hydrochloride,2.3 ml (16.5 mmol) of triethylamine and 2.43 g (5.5 mmol) of BOP areintroduced into 50 ml of dichloromethane containing 15 ml ofN,N-dimethylformamide. The reaction medium is stirred at ambienttemperature for 2 hours, evaporation is carried out and the residue isextracted with ethyl acetate. Washing is then carried out with water, apotassium acid sulfate solution, water, a sodium bicarbonate solution,water until a neutral pH is obtained, and a saturated sodium chloridesolution. Purification is subsequently carried out by chromatography onsilica (eluent: 100/3 dichloromethane/methanol).

In this way, 2.1 g of desired compound are obtained.

Yield: 71% NMR spectrum: standard

EXAMPLE 103-{[(2-Butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl)carbonyl]amino}propionicacid

2 g of methyl3-{[(2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl)-carbonyl]amino}propanoateand 0.270 g (2 equivalents) of sodium hydroxide are introduced into amixture of 50 ml of dioxane, then 10 ml of methanol and 10 ml of water.The mixture is stirred for 2 hours at ambient temperature, evaporationis carried out, and then the residue is taken up in water. Acidificationwith dilute hydrochloric acid, until a pH of approximately 5 isobtained, extraction with dichloromethane and washing with a saturatedsodium chloride solution are then carried out. Purification issubsequently carried out by chromatography on silica (eluent: 100/7dichloromethane/methanol).

In this way, 1.55 g of desired compound are obtained in the form of anamorphous solid.

Yield: 79% NMR spectrum: standard

EXAMPLE 112-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxamide

3.5 g of2-butyl-3-[4-[3-dibutylamino)propoxy]benzoyl]-5-cyano-1-benzofuran aremixed in 35 ml of concentrated sulfuric acid.

The reaction medium is stirred at ambient temperature for 24 hours andis then poured onto ice. Basification, under cold conditions, withsodium hydroxide and extraction with dichloromethane are carried out.Washing with a saturated sodium chloride solution and purification bycrystallization from heptane are then carried out.

In this way, 2.68 g of desired compound are obtained.

Yield: 74% M.p.: 90–92° C. NMR spectrum: standard

EXAMPLE 122-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-(1H-tetrazol-5-yl)-1-benzofuran

3.26 g of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-cyano-1-benzofuran and4.5 g (approximately 2 equivalents) of tributyltin azide are introducedinto 80 ml of toluene. The mixture is refluxed for 90 hours, the solventis evaporated off and the residue is chromatographed on silica (eluent:92/8 dichloromethane/methanol). Crystallization from diisopropyl etheris subsequently allowed to take place.

In this way, 3.05 g of desired compound are obtained.

Yield: 86% M.p.: 145–147° C. NMR spectrum: standard

EXAMPLE 132-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carbohydrazide

2.16 g (4.3 mmol) of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylicacid and 2.5 ml of thionyl chloride are introduced into 50 ml ofchloroform. The mixture is brought to reflux for 1 hour, and evaporationis carried out.

The residue is taken up in diethyl ether and the solvent is evaporatedoff. These two operations are repeated. The acyl chloride thus formed istaken up in 15 ml of tetrahydrofuran, and this solution is addeddropwise to a solution of 1 ml of hydrazine hydrate at 98% in 15 ml oftetrahydrofuran. The reaction medium is stirred at ambient temperatureand then evaporation is carried out. Extraction with ethyl acetate andwashing with water are carried out. Purification is subsequently carriedout by chromatography on silica (eluent: 85/5/0.2dichloromethane/methanol/aqueous ammonia).

In this way, 1.13 g of desired compound are obtained.

Yield: 41% NMR spectrum: standard

EXAMPLE 145-(2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-6-yl)-1,3,4-oxadiazol-2-(3H)-onehydrochloride

1.13 g of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carbohyrazideare dissolved in 20 ml of chloroform and this solution is added dropwiseto a solution of 2.2 g of phosgene in 30 ml of chloroform. The mixtureis brought to reflux for 6 hours. After the mixture has returned toambient temperature, washing is carried out first with water, until aneutral pH is obtained, and subsequently with a saturated sodiumbicarbonate solution.

In this way, 0.535 g of desired compound is obtained aftercrystallization from diethyl ether.

Yield: 45% NMR spectrum: standard

EXAMPLE 152-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carbaldehyde(E)-O-methyloxime oxalate A. 2-Butyl-5-hydroxymethylbenzofuran

2.32 g (0.01 mol) of methyl 2-butyl-1-benzofuran-5-carboxylate in 20 mlof diethyl ether are added dropwise to 0.400 g of lithium aluminumhydride in 20 ml of diethyl ether, and the mixture is then brought tothe reflux temperature of ether.

Once the addition has been completed, the mixture is stirred for 1 hourat ambient temperature. The mixture is cooled in an ice/water mixture,hydrolysis is carried out by means of a 1N hydrochloric acid solutionand separation is carried out by settling. Extraction with diethyl etherand washing with water and a saturated sodium chloride solution arecarried out.

In this way, 1.92 g of desired compound are obtained.

Yield: 94%

B. 2-Butyl-1-benzofuran-5-carbaldehyde

3.17 g (0.025 mol) of oxalyl chloride in 50 ml of dichloromethane arecooled to −60° C., and 3.67 g (0.054 mol) of dimethyl sulfoxide in 20 mlof dichloromethane are then added. The mixture is stirred for 10 minutesand 3.43 g (17 mmol) of 2-butyl-5-hydroxymethyl-1-benzofuran in 50 ml ofdichloromethane are then added. Stirring is carried out for 15 minutes,15.7 ml (0.113 mol) of triethylamine are added and the mixture isallowed to return to ambient temperature. Water is added and separationis carried out by settling. Extraction is carried out withdichloromethane. Washing is then carried out with water, a potassiumacid sulfate solution, until a neutral pH is obtained, with water, asodium carbonate solution, water and, finally, with a saturated sodiumchloride solution.

In this way, the desired compound is obtained, which is used in crudeform.

C. 2-Butyl-1-benzofuran-5-carbaldehyde (E)-O-methyloxime

2.07 g of 2-butyl-1-benzofuran-5-carbaldehyde, 1.38 g of methoxyaminehydrochloride and 1.57 g of pyridine are added to 25 ml of methanol. Themixture is stirred for 1.5 hours at ambient temperature, evaporation iscarried out and the residue is taken up in diethyl ether. Washing iscarried out with water, a potassium acid sulfate solution, water and asaturated sodium chloride solution. Purification is subsequently carriedout by chromatography on silica (eluent: 1/1 dichloromethane/heptane).

In this way, 1.96 g of desired compound are obtained.

Yield: 83%

D. 2-Butyl-3-[4-(3-bromopropoxy)benzoyl]-1-benzofuran-5-carbaldehyde(E)-O-methyloxime

Under argon, 6.94 g (2 equivalents) of ferric chloride are introducedinto 40 ml of dichloroethane. 4.91 g (21 mmol) of2-butyl-1-benzofuran-5-carbaldehyde (E)-O-methyloxime dissolved in 25 mlof dichloroethane are then added, at around +10° C., and 11.89 g (2equivalents) of 1-chlorocarbonyl-4-(3-bromopropoxy)benzene in 25 ml ofdichloromethane are then introduced at between +10 and +15° C. Themixture is allowed to return to ambient temperature and is then stirredfor 5 hours at ambient temperature. It is then poured onto an ice/watermixture, the precipitate is filtered off and the filtrate is separatedout by settling. Purification is then carried out by chromatography onsilica (eluent: dichloromethane).

In this way, the desired compound is obtained, that is to say 2.74 g of(E) isomer (yield: 27.5%) and 2.05 g of (Z) isomer.

M.p.: 78–81° C.

E.2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carbaldehyde(E)-O-methyloxime oxalate

2.3 g (5 mmol) of2-butyl-3-[4-(3-bromopropoxy)benzoyl]-1-benzofuran-5-carbaldehyde(E)-O-methyloxime, 1.28 g (2 equivalents) of dibutylamine, 1.38 g (2equivalents) of potassium carbonate and 0.75 g (1 equivalent) of sodiumiodide are added to 25 ml of acetonitrile. The mixture is brought toreflux for 4 hours and evaporated. Extraction is carried out with ethylacetate and washing is carried out with water and a saturated sodiumchloride solution. Purification is subsequently carried out bychromatography on silica (eluent: 100/2.5 dichloromethane/methanol),which gives 2.24 g (yield: 88%) of desired compound in the base form.

2.0 g of base thus obtained and 0.361 g of oxalic acid are then added tomethanol and evaporation is carried out. The residue is taken up indiethyl ether and crystallization is allowed to take place.

In this way, 2.25 g of desired compound are obtained.

Yield: 92% M.p.: 97–99° C. NMR spectrum: standard

EXAMPLE 162-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-hydroxymethyl-1-benzofuranoxalate A. Methyl2-butyl-3-[2-(4-hydroxyphenyl)-1,3-dioxolan-2-yl]-1-benzofuran-5-carboxylate

A mixture of 4.93 g (14 mmol) of methyl 2-butyl-3-(4-(ethylene glycolhydroxy)benzoyl)-1-benzofuran-5-carboxylate, 2.17 g and 0.500 g ofp-toluenesulfonic acid in 250 ml of benzene is brought to reflux.Dilution is carried out with diethyl ether and washing is carried outwith a sodium bicarbonate solution, water and a sodium chloridesolution. Drying and evaporation are carried out.

B.2-Butyl-5-hydroxymethyl-3-[2-(4-hydroxy-phenyl)-1,3-dioxolan-2-yl]-1-benzofuran

The crude product obtained in the preceding step, dissolved in 50 ml oftetrahydrofuran, is added dropwise to 1.4 g of lithium aluminum hydridein 50 ml of tetrahydrofuran.

The mixture is stirred for 2 hours at ambient temperature, hydrolysis iscarried out with a dilute solution of hydrochloric acid, until pH=3 isobtained, and separation is carried out by settling. Extraction withdiethyl ether and then washing with water and a saturated sodiumchloride solution are carried out.

In this way, the desired compound is obtained, which is used in thecrude form. However, this compound can be purified by chromatography onsilica (eluent: 100/2.5 dichloromethane/methanol).

M.p.: 100–101° C.

C. 2-Butyl-3-(4-hydroxybenzoyl)-5-hydroxymethyl-1-benzofuran

A solution formed by the crude product obtained in the preceding stepand 0.8 g of pyridine p-toluenesulfonate in 100 ml of acetone containing10 ml of water is brought to reflux for 3 hours. Evaporation is carriedout and the residue is taken up in a diethyl ether/water mixture. Theprecipitate obtained is filtered off and is washed with water anddiethyl ether, which gives a first crop of the desired product.

The organic phase is separated out by settling, and washing is carriedout with water, a sodium bicarbonate solution, water and a sodiumchloride solution.

Drying and evaporation are carried out, the residue is taken up withdiethyl ether and filtration is carried out, which gives a second cropof the desired product.

In this way, 3.37 g of desired compound are obtained aftercrystallization from diethyl ether.

Yield: 74% M.p.: 180–182° C.

D.2-Butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-5-hydroxymethyl-1-benzofuranoxalate

1.68 g of 2-butyl-3-(4-hydroxybenzoyl)-5-hydroxymethyl-1-benzofuran,1.18 g of 1-chloro-3-(dibutylamino)propane and 0.960 g of potassiumcarbonate are dissolved in 70 ml of methyl ethyl ketone. The mixture isbrought to reflux for 6 hours, water is added and separation is carriedout by settling. Extraction with ethyl acetate and washing with asaturated sodium chloride solution are carried out. Purification issubsequently carried out by chromatography on silica (eluent: 95/5dichloromethane/methanol), which gives the desired compound in the freebase form.

2.50 g of the base thus obtained are subsequently mixed with 0.455 g ofoxalic acid in methanol, evaporation is carried out and the residue istaken up in diethyl ether. Crystallization is allowed to take place, andfiltration and washing with diethyl ether are carried out.

In this way, 2.57 g of desired compound are obtained.

Yield: 85.5% NMR spectrum: standard

EXAMPLE 17 2-Butyl-3-[4-[3-(cis-3,5-diethyl-1-piperidinyl)propoxy]benzoyl-5-(3-methyl-1,2,4-oxadiazol-5-yl]-1-benzofuranA.2-Butyl-3-(4-hydroxybenzoyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-benzofuran

1.018 g of acetamide oxime, 0.660 g of sodium hydride, 6 g of molecularsieve and 60 ml of tetrahydrofuran are placed, under argon, in athree-necked round-bottomed flask. Heating is carried out at 60° C. for1 hour, 4.03 g of methyl2-butyl-3-(4-hydroxy-benzoyl)-1-benzofuran-5-carboxylate dissolved in 50ml of tetrahydrofuran are added and the mixture is brought to reflux for3 hours. The mixture is diluted with water, a sodium chloride solutionis added and extraction is carried out with ethyl acetate. Washing iscarried out with a saturated sodium chloride solution.

In this way, 3.4 g of desired compound are obtained in the crystallizedform.

Yield: 79% M.p.: 180–182° C.

B.2-Butyl-3-[4-(3-bromopropoxy)benzoyl]-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-benzofuran

4.26 g (0.0113 mol) of compound obtained in the preceding step, 11.44 g(5 equivalents) of 1,3-dibromopropane and 1.88 g (1.2 equivalents) ofpotassium carbonate are mixed in 100 ml of methyl ethyl ketone. Themixture is brought to reflux for 3 hours and is evaporated. The residueis taken up in water and extraction is carried out with ethyl acetate.Washing is carried out with a saturated sodium chloride solution andpurification is carried out by chromatography on silica (eluent: 100/3dichloromethane/methanol).

In this way, 3.58 g of desired compound are obtained.

Yield: 64% M.p.: 85–87° C.

C.2-Butyl-3-[4-[3-(cis-3,5-diethyl-1-piperidinyl)propoxy]benzoyl-5-(3-methyl-1,2,4-oxadiazol-5-yl]-1-benzofuran

3.4 g of compound obtained in the preceding step, 1.21 g (1.1equivalents) of cis-3,5-diethylpiperidine hydrochloride, 1.03 g (1equivalent) of sodium iodide and 2.83 g (3 equivalents) of potassiumcarbonate are introduced into 100 ml of acetonitrile. The mixture isbrought to reflux for 6 hours, diluted with water and separated bysettling. Extraction with ethyl acetate and washing with a saturatedsodium chloride solution are carried out. Purification is subsequentlycarried out by chromatography on silica (eluent: 100/2.5dichloromethane/methanol and 20% aqueous ammonia: 2 drops).

In this way, 2.55 g of desired compound are obtained.

Yield: 67% M.p.: 81–83° C. (after recrystallization from heptane) NMRspectrum: standard

EXAMPLE 18 Methyl 2-butyl-3-[4-[3-(cis-3,5-dimethyl-1-piperidinyl)propoxy]benzoyl]-1-benzofuran-6-carboxylatehydrochloride A. Isopropyl3-methoxy-4-trifluoromethanesulfon-yloxybenzoate

2.1 g (0.01 mol) of isopropyl 3-methoxy-4-hydroxybenzoate and 0.3 g (1.1equivalents) of pyridine are introduced into 20 ml of dichloromethane. Asolution of 3.1 g (1.1 equivalents) of trifluoromethanesulfonicanhydride in 10 ml of dichloromethane are then added dropwise, atbetween 0° C. and 5° C. The mixture is allowed to return to ambienttemperature and is stirred for 0.5 h at this temperature, andevaporation is carried out. Extraction with ethyl acetate and washingwith water, dilute hydrochloric acid, a sodium bicarbonate solution,water and, finally, a saturated sodium chloride solution are carriedout.

In this way, 3.22 g of desired compound are obtained.

Yield: 94%

B. Isopropyl 3-methoxy-4-(1-hexyn-1-yl)benzoate

3.18 g (9.3 mmol) of compound obtained in the preceding step, 1.52 g (2equivalents) of 1-hexine, 6.5 ml (approximately 5 equivalents) oftriethylamine and 0.325 g (0.05 equivalent) ofdichlorobis(triphenylphosphine)palladium are introduced into 25 ml ofN,N-dimethylformamide. The mixture is heated at 90° C. for 2 hours,diluted with water, and dilute hydrochloric acid is added. Extractionwith diethyl ether and washing with water and a saturated sodiumchloride solution are carried out. Purification is subsequently carriedout by chromatography on silica (eluent: 1/1 dichloromethane/heptane).

In this way, 1.35 g of desired compound are obtained.

Yield: 53%

C. 2-Butyl-1-benzofuran-6-carboxylic acid

9.62 g (35 mmol) of compound obtained in the preceding step areintroduced into 200 ml of dichloromethane and the mixture is cooled toapproximately −70° C. 70 ml (2 equivalents) of a solution of 1M borontribromide in dichloromethane are then added. The mixture is allowed toreturn to ambient temperature and is stirred for 1 hour at ambienttemperature. It is cooled by means of an ice/water mixture andhydrolysis is carried out. Extraction with dichloromethane and washingwith water and a saturated sodium chloride solution are carried out.Purification is subsequently carried out by chromatography on silica(eluent: 100/3 dichloromethane/methanol).

In this way, 2.5 g of desired compound are obtained.

Yield: 32.7% M.p.: 102–104° C.

D. Methyl 2-butyl-1-benzofuran-6-carboxylate

2.5 g of compound obtained in the preceding step are introduced into 80ml of methanol and 1 ml of concentrated sulfuric acid is added. Themixture is brought to reflux for 6 hours and evaporated. Extraction withdiethyl ether and washing with water, a sodium bicarbonate solution,water and a saturated sodium chloride solution are carried out.

In this way, 2.60 g of desired compound are obtained.

Yield: 98%

E. Methyl2-butyl-3-[4-(3-bromopropoxy)benzoyl]-1-benzofuran-6-carboxylate

2.60 g (11 mmol) of compound obtained in the preceding step and 4.58 g(1.5 equivalents) of 4-(3-bromopropoxy)benzoyl chloride are introducedinto 150 ml of dichloromethane. 2.2 ml of stannic chloride in 50 ml ofdichloromethane are then added, at a temperature of 15 to 20° C. Themixture is stirred at ambient temperature for 72 hours, poured onto anice/water mixture and filtered, and evaporation is carried out.Extraction with ethyl acetate and washing with a sodium carbonatesolution, with water and with a saturated sodium chloride solution arecarried out. Purification is then carried out by chromatography onsilica (eluent: 100/2 dichloromethane/ethyl acetate).

In this way, 3.95 g of desired compound are obtained.

Yield: 76%

F. Methyl2-butyl-3-[4-[3-(cis-3,5-dimethyl-1-piperidinyl)propoxy]benzoyl]-1-benzofuran-6-carboxylatehydrochloride

3.9 g (8.2 mmol) of compound obtained in the preceding step, 1.36 g (1.1equivalents) of cis-3,5-diethylpiperidine hydrochloride, 1.25 g (1equivalent) of sodium iodide and 3.42 g (3 equivalents) of potassiumcarbonate are introduced into 100 ml of acetonitrile. The mixture isbrought to reflux for 3 hours, diluted in water and separated bysettling. Extraction is carried out with ethyl acetate. Purification isthen carried out by chromatography on silica (eluent: 100/3/0.1dichloromethane/methanol/ammonia), which gives 3.36 g (yield: 81%) ofdesired compound in the base form (NMR spectrum: standard).

3.30 g of base thus obtained are then dissolved in diethyl ether and asolution of hydrogen chloride in diethyl ether is added. Filtration andthen washing with diethyl ether are carried out. Purification issubsequently carried out by crystallization from diethyl ether.

In this way, 2.74 g of desired compound are obtained.

Yield: 77% M.p.: 169–171° C. NMR spectrum: standard

The following compound was prepared by following the same protocol asabove:

Methyl2-butyl-3-[4-(1-piperidinyl)propoxy]benzoyl]-1-benzofuran-6-carboxylatehydrochloride (Example 19)

M.p.: 176–178° C. NMR spectrum: standard

EXAMPLE 20 Methyl2-butyl-3-(4-{2-[methyl(4-nitrophenethyl)amino]-ethoxy}benzoyl)-1-benzofuran-5-carboxylate

4.3 g (9.36 mmol) of methyl2-butyl-3-[4-(3-bromopropoxy)benzoyl]-1-benzofuran-6-carboxylate areintroduced into 50 ml of acetonitrile and 1.7 g (9.36 mmol) ofN-methyl-N-(4-nitrophenyl)ethylamine, 1.4 g (9.36 mmol) of sodium iodideand 2.58 g (18.7 mmol) of potassium carbonate are then added.

The mixture is brought to reflux for 18 hours, concentrated to drynessand extracted with ethyl acetate. Washing is carried out with water anda saturated sodium chloride solution, and then purification is carriedout by chromatography on silica (eluent: 99/1 and then 97/3dichloromethane/methanol).

In this way, 5.0 g of desired compound are obtained.

Yield: 95.6% NMR spectrum: standard

EXAMPLE 21 Methyl3-(4-{2-[(4-aminophenethyl)(methyl)amino]-ethoxy}benzoyl)-2-butyl-1-benzofuran-5-carboxylate

5.0 g of compound obtained in the preceding example are introduced into100 ml of absolute ethanol and a catalytic amount of Raney nickel isadded.

Hydrogenation is subsequently carried out under normal pressure and atambient temperature. When the reaction no longer evolves, filtrationover diatomaceous earth and rinsing with absolute ethanol are performed.Concentration is carried out, followed by purification by chromatographyon silica (eluent: 97/3 and then 95/5 dichloromethane/methanol).

In this way, 3.57 g of desired compound are obtained.

Yield: 75.5% NMR spectrum: standard

EXAMPLE 22 Methyl2-butyl-3-{4-[2-(methyl{4-[(methylsulfonyl)-amino]phenethyl}amino)ethoxy]benzoyl}-1-benzofuran-5-carboxylate

3.57 g (6.75 mmol) of compound obtained in the preceding step and 2.59 g(14.9 mmol) of methanesulfonic anhydride are introduced into 200 ml ofdichloromethane. The mixture is stirred at ambient temperature for 18hours and concentrated to dryness. The residue is taken up with a 2Nsodium bicarbonate solution and extraction is carried out with ethylacetate. Washing is carried out with water and a sodium chloridesolution, followed by purification by chromatography on silica (eluent:97/3 and then 50/50 dichloromethane/methanol and, finally, puremethanol).

In this way, 2.928 g of desired compound are obtained.

Yield: 71.5% NMR spectrum: standard

EXAMPLE 23 Methyl3-(5-cyano-3-{4-[3-(dibutylamino)propoxy]-benzoyl}-1-benzofuran-2-yl)propanoateoxalate A. 3-Iodo-4-hydroxybenzonitrile

11.9 g (0.1 mol) of 4-hydroxybenzonitrile are dissolved in 250 ml ofmethanol and 250 ml of 20% aqueous ammonia are added. A solution of31.75 g of iodine in 250 ml of methanol is then added dropwise, withcare, due to the explosive nature of the reaction. After addition, themixture is stirred for 2 hours at ambient temperature. The methanol isevaporated off, dilution is carried out in water and acidification witha hydrochloric acid solution is performed until pH=2 to 3 is obtained.Extraction with ethyl acetate and washing with water, a sodiumthiosulfate solution and a saturated sodium chloride solution aresubsequently carried out.

In this way, 24.73 g of desired compound are obtained.

M.p.: 144–146° C.

The compound below was prepared using the same process as above:

Isopropyl 3-iodo-4-hydroxybenzoate B. Methyl3-(5-cyano-1-benzofuran-2-yl)propanoate

19.38 g (79 mmol) of compound obtained in the preceding step, 9.81 g(1.1 equivalents) of methyl 4-pentanoate, 0.750 g (0.05 equivalent) ofcopper iodide, 2.77 g of dichlorobis(triphenylphosphine)-palladium and100 ml (10 equivalents) of tetramethylguanidine are introduced into 125ml of N,N-dimethylformamide. The mixture is stirred at ambienttemperature for 20 hours, diluted with 1000 ml of water and extractedwith 600 ml of ethyl acetate. Washing is carried out with water, dilutehydrochloric acid, water and a saturated sodium chloride solution.Purification is subsequently carried out by chromatography on silica(eluent: 100/1 dichloromethane/ethyl acetate).

In this way, 9.93 g of desired compound are obtained.

Yield: 59% M.p.: 91–92° C.

The following compound was obtained by following the same process asabove:

Methyl 3-(5-isopropoxycarbonyl-1-benzofuran-2-yl)propanoate

M.p.: 62–64° C.

C. Methyl 3-[5-cyano-3-(4-methoxybenzoyl)-1-benzofuran-2-yl]propanoate

9.91 g of compound obtained in the preceding step in 50 ml ofdichloroethane are added, at around +10° C., to a solution of 11.46 g(1.5 equivalents) of ferric chloride in 80 ml of dichloroethanemaintained under argon, and then 12.03 g (1.5 equivalents) of anisoylchloride in 50 ml of dichloroethane are introduced, at a temperature of+10 to +15° C. The mixture is allowed to return to ambient temperatureand is then stirred, at this temperature, for 5 hours. It is poured ontoan ice/water mixture, the precipitate is filtered off and the filtrateis separated out by settling. The aqueous phase is extracted withdichloromethane and the organic phases are washed, which organic phasesare purified by chromatography on silica (eluent: 100/2dichloromethane/ethyl acetate).

In this way, 10.78 g of desired compound are obtained.

Yield: 64% M.p.: 95–98° C.

D. Methyl 3-[5-cyano-3-(4-hydroxybenzoyl)-1-benzofuran-2-yl]propanoate

9.73 g of compound obtained in the preceding step and 10.8 g of aluminumchloride are introduced into 350 ml of toluene. The mixture is heated at80° C. for 6 hours and then separated by settling. The residue is takenup in tetrahydrofuran and ice is added gently. Separation is carried outby settling, the aqueous phase is extracted with ethyl acetate and thethree organic phases are pooled. Washing is carried out with water,followed by purification by chromatography on silica (eluent: 95/5 andthen 90/10 dichloromethane/ethyl acetate.

In this way, 5.57 g of desired compound are obtained.

Yield: 95% M.p.: 156–158° C.

E. Methyl3-(5-cyano-3-{4-[3-(dibutylamino)-propoxy]benzoyl}-1-benzofuran-2-yl)propanoateoxalate

4.54 g (13 mmol) of compound obtained in the preceding step, 2.95 g (1.1equivalents) of 3-chloro-1-(dibutylamino)propane and 2.16 g (1.2equivalents) of potassium carbonate are introduced into 70 ml of methylethyl ketone. The mixture is brought to reflux for 6 hours, thendilution with water and extraction with ethyl acetate are carried out.Washing is carried out with a saturated sodium chloride solution,followed by purification by chromatography on silica (eluent: 5/5heptane/ethyl acetate, 95/3 and then 90/10 dichloromethane/methanol),which gives 6.65 g of the desired compound in the free base form. A 2.32g sample of this base is taken and introduced into methanol. 0.416 g ofoxalic acid is added thereto and evaporation is carried out. The residueis taken up in diethyl ether and evaporation is carried out.Purification is subsequently carried out by crystallization from diethylether.

In this way, 2.4 g of desired compound are obtained.

Yield: 87% M.p.: 76–79° C. NMR spectrum: standard

The product below is obtained by following the same process as above,but using hydrochloric acid instead of oxalic acid:

-   Methyl    3-(4-{3-[cis-3,5-diethylpiperidinyl]propoxy}benzoyl)-2-(3-methoxy-3-oxopropyl)-1-benzofuran-5-carboxylate    hydrochloride (Example 24)

Yield: 81% M.p.: 166–169° C. (after crystallization from diethyl ether)

NMR spectrum: standard

EXAMPLE 252-Butyl-5-cyano-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuranoxalate A. 2-Methoxy-5-cyanobenzaldehyde

A mixture of 40.63 g of 2-methoxy-5-bromo-benzaldehyde, 13.35 g of zinccyanide and 8.7 g of tetrakis(triphenylphosphine)palladium in 240 ml ofdeoxygenated N,N-dimethylformamide is heated, under argon, for 3 hours.The mixture is allowed to return to ambient temperature and extractionis carried out with 600 ml of toluene. Washing is subsequently carriedout with twice 600 ml of 2N aqueous ammonia and then with a saturatedsodium chloride solution. Purification is then carried out bycrystallization from diisopropyl ether.

In this way, 30.2 g of desired compound are obtained.

Yield: 99% M.p.: 115–118° C.

B. 2-Hydroxy-5-cyanobenzaldehyde

31.08 g of compound obtained in the preceding step and 24.52 g oflithium chloride are introduced into 500 ml of N,N-dimethylformamide.The mixture is brought to reflux for 2 hours and the solvent isevaporated off. The residue is taken up in a potassium acid sulfatesolution and extraction is carried out with ethyl acetate. Washing isthen carried out with water and a saturated sodium chloride solution.

In this way, 24.5 g of desired compound are obtained.

Yield: 86%

C. Methyl 2-(2-formyl-4-cyanophenoxy)hexanoate

24.5 g of compound obtained in the preceding step, 47.52 g of methyl2-bromohexanoate and 28.8 g of potassium carbonate are placed in 400 mlof N,N-dimethylformamide. The mixture is heated at approximately 80° C.for 1.5 hours and the solvent is evaporated off. The residue is taken upin a potassium acid sulfate solution and extraction is carried out withethyl acetate. Washing is then carried out with water and a saturatedsodium chloride solution.

In this way, 53.6 g of desired compound are obtained in the crude form.

M.p.: 77–79° C.

D. 2-(2-Formyl-4-cyanophenoxy)hexanoic acid

53.6 g of crude compound obtained in the preceding step and 8.6 g ofsodium hydroxide are introduced into 320 ml of methanol containing 200ml of dioxane and 160 ml of water. The mixture is stirred for 1.5 hoursat ambient temperature and evaporation is carried out. The residue istaken up in water containing concentrated hydrochloric acid andextraction is carried out with ethyl acetate. Washing is then carriedout with water and a saturated sodium chloride solution.

In this way, 52.1 g of desired compound are obtained in the crude form.

E. 2-Butyl-5-cyano-1-benzofuran

47.66 g of benzenesulfonyl chloride are introduced into 100 ml oftoluene and 68.23 g of triethylamine in 50 ml of toluene are added. Themixture is heated to 80° C. and then 52.1 g of compound obtained in thepreceding step dissolved in 400 ml of toluene are added dropwise at atemperature of less than 90° C. As soon as the addition is finished, theheating is continued for 0.5 hours and then the mixture is allowed toturn to ambient temperature. Washing is carried out with water and theaqueous phase is extracted with toluene. The pooled organic phases areagitated with 100 ml of 2N sodium hydroxide and separation is carriedout by settling. Extraction with toluene and washing with water, apotassium bisulfate solution, water and a saturated sodium chloridesolution are carried out. Purification is then carried out bychromatography on silica (eluent: dichloromethane).

In this way, 19.94 g of desired compound are obtained.

Overall yield for the 5 steps: 53%

F. 2-Butyl-5-cyano-3-(4-methoxybenzoyl)-1-benzofuran

32.43 g (2 equivalents) of ferric chloride are introduced into 200 ml ofdichloroethane, under argon. 19.92 g of compound obtained in thepreceding step are then added, at around 10° C., and 34.36 g (2equivalents) of anisoyl chloride dissolved in 200 ml of dichloroethaneare then introduced at a temperature of between +10 and +15° C. Themixture is allowed to return to ambient temperature and stirred at thistemperature for 16 hours. It is poured onto an ice/water mixture andfiltration is carried out over sintered glass. The filtrate is separatedby settling, the aqueous phase is extracted with dichloromethane and theorganic phases are mixed. Washing is carried out with a dilute sodiumbicarbonate solution, water and a saturated sodium chloride solution.Purification is subsequently carried out by chromatography on silica(eluent: dichloromethane).

In this way, 24.87 g of desired compound are obtained.

Yield: 74.5%

G. 2-Butyl-5-cyano-3-(4-hydroxybenzoyl)-1-benzofuran

16.27 g of compound obtained in the preceding step and 19.9 g ofaluminum chloride are introduced into 200 ml of toluene. The mixture isheated at 60° C. for 2 hours and the toluene is separated by settling.The residue is dissolved in tetrahydrofuran and a water/ice mixture isadded. The mixture is stirred for 1 hour and separated by settling, andthe aqueous phase is extracted with ethyl acetate. The 3 organic phasesare then mixed and washing is carried out with water and a sodiumchloride solution. Purification is subsequently carried out bycrystallization from heptane.

In this way, 14.05 g of desired compound are obtained.

Yield: 90% M.p.: 152–153° C.

H. 2-Butyl-5-cyano-3-[4-[3-(dibutylamino)-propoxy]benzoyl]-1-benzofuran

2.02 g of compound obtained in the preceding step, 1.45 q of3-chloro-1-(dibutylamino)propane and 1.06 g of potassium carbonate areintroduced into 30 ml of methyl ethyl ketone. The mixture is brought toreflux for 6 hours and water is added. The mixture is separated bysettling and the aqueous phase is extracted with ethyl acetate. Thepooled aqueous phases are washed with a saturated sodium chloridesolution and extraction is carried out with ethyl acetate. Purificationis subsequently carried out by chromatography on alumina (eluent: 95/5heptane/ethyl acetate), which gives the desired compound in the freebase form (2.25 g; yield: 72%). 1.86 g of this base compound and 0.343 gof oxalic acid dissolved in methanol are then mixed. The mixture isevaporated and diethyl ether is added. The mixture is stirred for a fewhours, and filtration and washing with diethyl ether are carried out.Crystallization is then allowed to take place.

In this way, 2.11 g of desired compound of oxalate are obtained.

Yield: 96% M.p.: 85–87° C. NMR spectrum: standard

EXAMPLE 26 Methyl3-{[(2-butyl-3-{4-[3-(neopentylamino)propoxy]-benzoyl}-1-benzofuran-5-yl)carbonyl]amino}propanoateA. Methyl2-butyl-3-{4-[3-[(N-neopentyl-N-tert-butoxycarbonyl)amino]propoxy]benzoyl}-1-benzofuran-5-carboxylate

8.57 g (18 mmol) of2-butyl-3-[4-[3-(neopentylamino)propoxy]benzoyl]-5-methoxycarbonyl-benzofuranand 4.29 g (1.1 equivalents) of tert-butoxy-carboxylic acid anhydrideare introduced into 100 ml of chloroform. The mixture is brought toreflux for 3 hours and then evaporation is carried out.

In this way, the desired product is obtained in the crude form.

B.2-Butyl-3-{4-[3-[(N-neopentyl-N-tert-butoxy-carbonyl)amino]propoxy]benzoyl}-1-benzofuran-5-carboxylicacid

The crude product obtained in the preceding step is dissolved in 200 mlof dioxane containing 40 ml of methanol and 40 ml of water. 1.45 g(approximately 2 equivalents) of sodium hydroxide are added and themixture is then stirred at ambient temperature for 48 hours. Evaporationis carried out, the residue is taken up in water and a potassiumhydrogen sulfate solution is used to acidify. Extraction with ethylacetate and washing with water and a saturated sodium chloride solutionare carried out.

In this way, 11.23 g of desired product are obtained in the crude form.

Yield: 100%

C. Methyl3-{[(2-butyl-3-{4-[3-[(N-neopentyl-N-tert-butoxycarbonyl)amino]propoxy]benzoyl}-1-benzofuran-5-yl)carbonyl]amino}propanoate

7.48 g of crude product obtained in the preceding step, 2 q (1.1equivalents) of methyl 3-aminopropanoate hydrochloride, 4.5 g oftriethylamine and 6.32 g (1.1 equivalents) of BOP are introduced into150 ml of dichloromethane. The mixture is stirred for 3 hours at ambienttemperature and then evaporation is carried out. Extraction with ethylacetate and washing with water, a potassium hydrogen sulfate solution,water, a sodium carbonate solution, water and, finally, a saturatedsodium chloride solution are carried out. Purification is subsequentlycarried out by chromatography on silica (eluent: 85/15dichloromethane/ethyl acetate).

In this way, 6.2 g of desired product are obtained in the crude form.Global yield of the 3 steps: 79.5%

D. Methyl3-{[(2-butyl-3-{4-[3-(neopentylamino)-propoxy]benzoyl}-1-benzofuran-5-yl)carbonyl]amino}propanoate

6.15 g of product obtained in the preceding step are dissolved in 50 mlof dichloromethane. The solution is cooled by means of an ice/water bathand 50 ml of trifluoroacetic acid are added. The mixture is stirred atambient temperature for 1 hour, evaporation is carried out, and theresidue is taken up in diethyl ether. Evaporation is carried out twomore times. Purification is then carried out by chromatography on silica(eluent: 100/5/0.2 dichloromethane/methanol/aqueous ammonia).

In this way, 4.5 g of desired compound are obtained.

Yield: 78%

EXAMPLE 27 Methyl2-{[(2-butyl-3-{4-[3-(dibutylamino)propoxy]-benzoyl}-1-benzofuran-5-yl)carbonyl]amino}benzoateoxalate

6.28 g (0.012 mol) of2-butyl-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-5-carboxylicacid are dissolved in 150 ml of chloroform. 6 ml of thionyl chloride arethen added and the mixture is brought to reflux for 3 hours. Evaporationis carried out then the residue is taken up in diethyl ether, 3 times.The crude acyl chloride thus formed is subsequently introduced into 130ml of dichloromethane and 9 g (0.06 mol) of 2-methoxycarbonylaniline areadded. The reaction medium is maintained at ambient temperature for 12hours and evaporation is carried out. Extraction with ethyl acetate andwashing with a dilute potassium carbonate solution, water and a sodiumchloride solution are carried out. Purification is then carried out bychromatography on silica (eluent: 96/4 dichloromethane/methanol), whichgives 5.26 g of desired product in the base form (yield: 68%). 2 g (3.1mmol) of base product thus obtained are then dissolved in 15 ml ofabsolute ethanol and 0.281 g (3.1 mmol) of oxalic acid is dissolved in10 ml of absolute ethanol. The two solutions are mixed and evaporationis carried out. The residue is taken up in diethyl ether andcrystallization is allowed to take place. The precipitate formed isfiltered off and dried.

In this way, 1.9 g of desired compound are obtained.

Yield: 84% M.p.: 89° C. NMR spectrum: standard

EXAMPLE 282-{[(2-Butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl)carbonyl]amino}benzoicacid hydrochloride

3.26 g (5.1 mmol) of methyl2-{[(2-butyl-3-{4-[3-(dibutylamino)propoxy]benzoyl}-1-benzofuran-5-yl]carbonyl]amino}benzoateoxalate are dissolved in 20 ml of dioxane.

0.407 g (10 mmol) of sodium hydroxide in 4 ml of water containing 4 mlof methanol are added. The medium is then left to stand at ambienttemperature for 4 hours and then filtered. Extraction with ethyl acetateand then washing with water, a 1N hydrochloric acid solution, water anda sodium chloride solution are carried out. Purification is subsequentlycarried out by chromatography on silica (eluent: 96/4dichloromethane/methanol).

In this way, 2.06 [lacuna] of desired product are obtained.

Yield: 61% M.p.: 109° C. NMR spectrum: standard

EXAMPLE 29 Isopropyl2-butyl-3-(4-{3-[cis-3,5-diethylpiperidinyl]-propoxy}benzyl)-1-benzofuran-5-carboxylateoxalate

3.19 g (4.89 mmol) of isopropyl2-butyl-3-(4-{3-[cis-3,5-diethylpiperidinyl]propoxy}benzoyl)-1-benzofuran-5-carboxylateare introduced into 50 ml of isopropanol and then 1 spoonful ofpalladium charcoal at 10% and a few drops of concentrated hydrochloricacid are added successively. Hydrogenation is subsequently carried outunder normal pressure for 48 hours at 45° C. The mixture is pulled dryover diatomaceous earth, and the product is rinsed with isopropanol,filtered and concentrated. Purification is then carried out bychromatography on silica (eluent: dichloromethane/methanol), which gives1.533 g (yield: 49.1%) of the desired compound in the base form.

1.32 g (2.41 mmol) of base compound thus obtained are introduced into aminimal amount of ethanol to ensure dissolution thereof and 0.217 g(2.41 mmol) of oxalic acid is added. The mixture is concentrated andtriturated in diethyl ether, and the product is filtered and dried.Purification is then carried out by crystallization.

In this way, 1.203 g of desired compound are obtained.

Yield: 78.3% M.p.: 148–149° C. NMR spectrum: standard

EXAMPLE 30 Methyl2-butyl-3-[4-(cis-3,5-dimethyl-1-piperidinyl)-propoxy]benzoyl]-1-benzofuran-4-carboxylatehydrochloride A) Methyl 2-hydroxy-3-methoxybenzoate

25.5 g (0.152 mol) of 2-hydroxy-3-methoxy-benzoic acid are introducedinto 250 ml of methanol containing 1 ml of sulfuric acid. The mixture isbrought to reflux for 4 days, concentrated to dryness and then extractedwith ethyl acetate. Washing is then carried out with water, a 10% sodiumcarbonate solution, water and a sodium chloride solution.

In this way, 25.2 g of desired compound are obtained.

Yield: 91.2% M.p.: 68–69° C.

B) Methyl 2-trifluoromethanesulfonyloxy-3-methoxybenzoate

25 g (0.137 mol) of compound obtained in the preceding step areintroduced into 200 ml of dichloromethane and 11.93 g (0.151 mol) ofpyridine are added. A mixture of 42.6 g (0.151 mol) of triflic anhydridein 200 ml of dichloromethane is then added, at a temperature of 0° C. to5° C. The mixture is stirred at ambient temperature for 3 hours,concentrated to dryness and extracted with diethyl ether. Washing isthen carried out with water, dilute hydrochloric acid, water, a dilutesodium bicarbonate solution, water and a sodium chloride solution.Purification is then carried out by chromatography on silica (eluent:5/5 dichloromethane/heptane).

In this way, 19.36 g of desired compound are obtained.

Yield: 54.9%

C) Methyl 2-(1-hexynyl)-3-methoxybenzoate

19.26 g (74.9 mmol) of compound obtained in the preceding step areintroduced into 200 ml of N,N-dimethylformamide and then 12.3 g (16.85ml; 149.7 mmol) [lacuna], 37.94 g (52.2 ml; 375 mmol) of triethylamineand 2.62 g (3.74 mmol) of dichlorobis-(triphenylphosphine)palladium areadded. The mixture is heated at 90° C. for 3 hours, then diluted withwater and extracted with diethyl ether. Washing is then carried out withdilute hydrochloric acid, water and a sodium chloride solution.Purification is then carried out by chromatography on silica (eluent:5/5 dichloromethane/heptane and then dichloromethane).

In this way, 6.1 g of desired compound are obtained.

Yield: 33.1%

D) Methyl 2-butyl-1-benzofuran-4-carboxylate

5.45 g (22.1 mmol) of compound obtained in the preceding step areintroduced into 100 ml of dichloromethane. 44.5 ml of a molar solutionof bromine tribromide in dichloromethane are then added, at atemperature of approximately −5° C. The mixture is stirred at ambienttemperature for 4 hours, and then water is added with care, whilemaintaining the temperature below 30° C. The mixture is subsequentlyextracted with dichloromethane and purification is carried out bychromatography on silica (eluent: dichloromethane).

In this way, 2 g of the desired compound are obtained.

Yield: 39%

E) Methyl2-butyl-3-[4-(3-bromopropoxy)benzoyl]-1-benzofuran-4-carboxylate

4 g (17.2 mmol) of the compound obtained in the preceding step areintroduced into 50 ml of dichloroethane and 7.2 g (25.8 mmol) of4-(3-bromopropoxy)benzoyl chloride are added. 3.44 ml (25.8 mmol) of tintetrachloride are then added, at between 150 and 20° C. The mixture isstirred for 18 hours and diluted with dichloromethane. This mixture iswashed with water and an aqueous sodium chloride solution andconcentrated, and the product is taken up with ethyl acetate. Washing isthen carried out several times with a dilute aqueous solution of sodiumbicarbonate, with water and then with a sodium chloride solution. Theproduct is dried and concentrated. Purification is then carried out bychromatography on silica (eluent: dichloromethane).

In this way, 5.66 g of desired compound are obtained.

Yield: 69.5%

F) Methyl 2-butyl-3-[4-(cis-3,5-dimethyl-1-piperidinyl)propoxy]benzoyl]-1-benzofuran-4-carboxylatehydrochloride

2.8 g (5.9 mmol) of compound obtained in the preceding step areintroduced into 100 ml of acetonitrile and then 0.979 g (1.1equivalents) of cis-3,5-diethylpiperidine hydrochloride, 0.899 g (1equivalent) of sodium iodide and 2.46 g (3 equivalents) of potassiumcarbonate are added. The mixture is brought to reflux for 2 hours andthen diluted with ethyl acetate. Washing is carried out with water and asodium chloride solution, and then purification is carried out bychromatography on silica (eluent: 98/2/0.1dichloromethane/methanol/aqueous ammonia), which gives 2.137 g (yield:71.6%) of the desired compound in the free base form.

2.117 g of this base compound are then dissolved in the minimum amountof diethyl ether, and the amount of diethyl ether, containing hydrogenchloride, required to cause complete precipitation of the hydrochlorideis then added. The hydrochloride formed is filtered and then dried.

In this way, 2.078 [lacuna] of the desired compound are obtained.

Yield: 91.56% M.p.: 135–136° C. NMR spectrum: standard

Methyl2-butyl-3-[4-(3-(1-piperidinyl)propoxy]benzoyl]-1-benzofuran-4-carboxylateoxalate (Example 31) was prepared using the same process as above.

M.p.: 160° C. NMR spectrum: standard

EXAMPLE 323-(5-Cyano-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-2-yl)propanoicacid hydrochloride

A mixture of 3.55 g of methyl3-(5-cyano-3-[4-[3-(dibutylamino)propoxy]benzoyl]-1-benzofuran-2-yl)propanoateand 4.08 g (1 equivalent) of tributyltin oxide is heated at 100° C. for2.5 hours. It is diluted with water and extracted with ethyl acetate,and the extract is concentrated, which gives 3.17 g (yield: 91.5%) ofdesired compound in the base form.

3.1 g of this base compound are then dissolved in ethyl acetate, asolution of hydrogen chloride in diethyl ether is added until a slightlyacid pH is obtained, and crystallization from the ethyl acetate isallowed to take place. The product is filtered, washed with ethylacetate and dried under vacuum.

In this way, 2.35 g of desired compound are obtained.

Yield: 70.5% M.p.: 165–168° C. (ethyl acetate) NMR spectrum: standard

EXAMPLE 154(2-Butyl-3-(2-[4-(2-dibutylaminoethoxy)phenyl]-1,3-dioxolan-2-yl)benzofuran-5-yl)methanolOxalate A. Methyl3-(2-[4-(2-bromoethoxy)phenyl]-1,3-dioxolan-2-yl)-2-butylbenzofuran-5-carboxylate

10.0 g (0.022 mol) of methyl3-[4-(2-bromoethoxy)benzoyl]-2-butylbenzofuran-5-carboxylate, 3.39 g(0.055 mol) of ethylene glycol, 890 mg of para-toluenesulfonic acid(pTsA) and 100 ml of benzene are brought to reflux for 3 days,eliminating the water formed using a Dean-Stark apparatus. The mixtureis evaporated to dryness and the residue is chromatographed on a columnof silica, eluting with DCM (dichloromethane) and then a DCM/ethylacetate (99/1) mixture. 5 g of the pure desired compound are thusisolated.

B.(3-(2-[4-(2-Bromoethoxy)phenyl]-1,3-dioxolan-2-yl)-2-butylbenzofuran-5-yl)methanol

4.87 g (0.097 mol) of the compound obtained in the preceding step A aredissolved in 20 ml of anhydrous THF, under argon, and the mixture iscooled to −70° C. 32 ml of a solution of diisobutylaluminum hydride(DIBAL) in toluene are added at this temperature. After the addition hasbeen completed, the mixture is stirred for a further 1 hour at −70° C. 1ml of methanol is then added, at −70° C., and then, when gas is nolonger being given off, water is added. Filtration is carried outthrough celite. The gel and celite are washed 3 times with ethylacetate. The organic phase is separated by settling and the aqueousphase is then reextracted with ethyl acetate. The pooled organic phasesare washed with water and an aqueous NaCl solution. Drying is carriedout over Na₂SO₄. Purification is carried out by chromatography on silica(eluent: DCM/ethyl acetate at 92/8).

In this way, a total of 3.25 g of the desired compound are obtained.

C.(2-Butyl-3-(2-[4-(2-dibutylaminoethoxy)-phenyl]-1,3-dioxolan-2-yl)benzofuran-5-yl)-methanol

3.25 g of the compound obtained in the preceding step, 2.64 g ofdibutylamine, 1.02 g of sodium iodide, 2.83 g of potassium carbonate and50 ml of acetonitrile are mixed, and the mixture is refluxed for 3hours. It is evaporated to dryness, the residue is taken up with ethylacetate and washing is carried out with water and an aqueous NaClsolution. Drying is carried out over Na₂SO₄. Purification is carried outby chromatography on silica (eluent: DCM/methanol at 95/5).

In this way, 1.84 g of the desired compound are obtained.

D.2-Butyl-3-(2-[4-(2-dibutylaminoethoxy)-phenyl]-1,3-dioxolan-2-yl)benzofuran-5-yl)methanoloxalate

1.84 g of the compound obtained in the preceding step C and 313 mg ofoxalic acid in 20 ml of methanol are mixed. The mixture is evaporated.After trituration in ether, the powder is filtered over sintered glass.Drying is carried out under vacuum.

In this way, 1.7 g of the desired compound are obtained.

NMR spectrum: standard; see below

EXAMPLE 155 Isopropyl2-butyl-3-[4-(3-dibutylamino-2-hydroxy-propoxy)benzoyl]benzofuran-5-carboxylateoxalate A. Isopropyl2-butyl-3-(4-oxiranylmethoxy-benzoyl)benzofuran-5-carboxylate

A mixture of 3.15 g of isopropyl2-butyl-3-(4-hydroxybenzoyl)benzofuran-5-carboxylate, 25 ml ofisopropanol, 15 ml of epibromohydrin and 365 mg (1.1 equivalents) ofNaOH is brought to reflux for 1 hour. The mixture is evaporated, and theresidue is taken up with water and extracted 3 times with ethyl acetate.The extract is washed with water and then with a saturated NaClsolution. Drying is carried out over Na₂SO₄ and the product isconcentrated. Purification is carried out by chromatography on silica(eluent: ethyl acetate/dichloromethane).

In this way, 3.15 g of the desired compound are obtained.

B. Isopropyl2-butyl-3-[4-(3-dibutylamino-2-hydroxypropoxy)benzoyl]benzofuran-5-carboxylate

3.15 g of the compound obtained in the preceding step A, 3.15 g ofdibutylamine and 20 ml of acetonitrile are mixed and the mixture isbrought to reflux for 16 hours. The solvent is evaporated off andpurification is carried out by chromatography on silica (eluent: ethylacetate/dichloromethane and then methanol/dichloromethane).

In this way, 3.6 g of the desired compound are obtained.

C. Isopropyl2-butyl-3-[4-(3-dibutylamino-2-hydroxypropoxy)benzoyl]benzofuran-5-carboxylateoxalate

3.6 g of the compound obtained in the preceding step B and 585 mg ofoxalic acid in methanol are mixed. The mixture is evaporated. Aftertrituration in ether, the powder is filtered over sintered glass. Dryingis carried out under vacuum.

In this way, 2.1 g of the desired compound are obtained.

M.p.: 87–88° C. NMR spectrum: standard

EXAMPLE 158 2-Piperidin-1-ylethyl2-butyl-3-[4-(3-piperidin-1-ylpropoxy)benzoyl]benzofuran-5-carboxylatehydrochloride A. 2-Piperidin-1-ylethyl2-butyl-3-[4-(3-piperidin-1-ylpropoxy)benzoyl]benzofuran-5-carboxylate

7.5 g (0.016 mol) of2-butyl-3-[4-(3-piperidin-1-ylpropoxy)benzoyl]benzofuran-5-carboxylicacid are dissolved in 50 ml CHCl₃. 15 ml of SOCl₂ are added. The mixtureis brought to reflux for 3 hours. Evaporation is carried out and theresidue is taken up three times in ether. The product is taken up in 50ml of DCM. 2.34 ml of 2-(N-piperidyl)-1-ethanol (2.27 g; 0.0176 mol) areadded and the mixture is stirred for 24 hours at ambient temperature.Evaporation is carried out, the residue is taken up with ethyl acetateand the mixture is washed with water, a solution of NaOH, H₂O and asolution of NaCl. Purification is carried out by chromatography onsilica (eluent: DCM/methanol/NH₄OH: 92/8/0.5).

In this way, 2.32 g of the desired compound are obtained.

Yield: 25%

B. 2-Piperidin-1-ylethyl2-butyl-3-[4-(3-piperidin-1-ylpropoxy)benzoyl]benzofuran-5-carboxylatehydrochloride

2.3 g (0.004 mol) of the compound obtained in the preceding step A aredissolved in a mixture of ether and ethyl acetate. A solution ofhydrochloric acid dissolved in ether is added. The mixture isevaporated, the residue is taken up in ether and filtration is carriedout.

In this way, 2.02 g of the desired compound are obtained.

Yield: 78%

The compounds listed below were prepared using the processes describedin the preceding examples. For each of these compounds, the NMR spectraproved to be in accordance with the described structures.

R Am′ n′ Characteristics Ex.

—N(C₄H₉)₂ 3 Oxalate 33 H₅C₂—O—CO—

2 HydrochlorideM.p.: 133° C. 34 H₅C₂O—CO—

3 HydrochlorideM.p.: 164° C. 35

—N(C₄H₉)₂ 3 Oxalate 36 H₅C₂—NH—CO— —N(C₄H₉)₂ 3 OxalateM.p.: 85° C. 37neo-H₁₁C₅—O—CO— —N(C₄H₉)₂ 3 OxalateM.p.: 102° C. 38

—N(C₄H₉)₂ 3 OxalateM.p.: 99° C. 39 i-H₉C₄—O—CO— —N(C₄H₉)₂ 3 OxalateM.p.:98° C. 40 (i-H₇C₃)₂—CH—CO—

3 OxalateM.p.: 105° C. 41 t-H₉C₄—CO₂—

3 OxalateM.p.: 166° C. 42

3 Oxalate(amorphouswhite solid) 43 n-H₇C₃—CO₂— —N(C₄H₉)₂ 3Oxalate(amorphoussolid) 44

—N(C₄H₉)₂ 3 Oxalate(amorphoussolid) 45 (CH₃)₂N—(CH₂)₂—NH—CO— —N(C₄H₉)₂ 3Oxalate 46 H₅C₂—CO₂—

3 HydrochlorideM.p.: 161–163° C. 47 H₅C₂—CO₂—

2 HydrochlorideM.p.: 147–1503° C. 48 (CH₃)₂N—(CH₂)₂—CO₂—

3 Dioxalate(solid) 49 (CH₃)₂N—(CH₂)₂—CO₂—

3 Dihydrochlo-ride (solid) 50 CH₃O₂C—(CH₂)₂—NH—CO— —N(C₄H₉)₂ 3Oxalate(amorphoussolid) 51 HOCH₂—

2 Oxalate(amorphoussolid) 52 HOCH₂—

3 HydrochlorideM.p.: 173–175° C. 53

—N(C₄H₉)₂ 3 OxalateM.p.: 80° C. 54

—N(C₄H₉)₂ 3 BaseM.p.: 130° C. 55

—N(C₄H₉)₂ 3 HydrochlorideM.p.: 142° C. 56

—N(C₄H₉)₂ 3 OxalateM.p.: 86° C. 57

—N(C₄H₉)₂ 3 SolidM.p.: 89–91° C. 150 H₅C₂—CO₂—

2 HydrochlorideSolid M.p.:133–134° C. 156

3 HydrochlorideSolid 158 HOOC—

3 HydrochlorideAmorphous 162

Am′ n′ Characteristics Ex. —N(C₄H₉-n)₂ 2 OxalateM.p.: 88° C. 58

2 OxalateM.p.: 124° C. 59

3 BaseM.p.: 66–68° C. 60

2 HydrochlorideM.p.: 153° C. 61

2 HydrochlorideM.p.: 122° C. 62

3 HydrochlorideM.p.: 147° C. 63 —N(C₂H₅)₂ 2 HydrochlorideM.p.: 112° C.64 —N(C₂H₅)₂ 3 Hydrochloride 65 M.p.: 105° C.

2 OxalateM.p.: 185° C. 66

3 OxalateM.p.: 142° C. 67

3 OxalateM.p.: 155° C. 68

3 Oxalate(amorphouspowder) 69

3 OxalateM.p.: 116° C. 70

2 BaseM.p.: 124° C. 71

3 OxalateM.p.: 159° C. 72

3 HydrochlorideM.p.: 135° C. 73

2 HydrochlorideM.p.: 161° C. 74

2 HydrochlorideM.p.: 133° C. 75

3 Oxalate(amorphouspowder) 76

3 HydrochlorideM.p.: 141° C. 77

3 Oxalate (solid) 78

3 OxalateM.p.: 150–152° C. 79

3 Oxalate (solid) 80

2 HydrochlorideM.p.: 108–110° C. 81

2 Hydrochloride SolidM.p.: 153–156° C. 157

3 Hydrochloride SolidM.p.: 131–133° C. 159

Am′ n′ Characteristics Ex.

3 Oxalate(amorphous solid) 82 —NHC₄H₉-n 3 HydrochlorideM.p.: 176° C. 83

2 OxalateM.p.: 148° C. 84

3 OxalateM.p.: 161° C. 85

3 Oxalate(amorphous solid) 86

Am′ n′ Characteristics Ex. —N(C₄H₉-n)₂ 3 OxalateM.p.: 94° C. 87

3 OxalateM.p.: 85° C. 88

3 Hydrochloride(amorphous solid) 89

3 TrihydrochlorideM.p.: 242° C. 90

3 OxalateM.p.: 163° C. 91

3 Hydrochloride(amorphous solid) 92

3 Hydrochloride(amorphous solid) 93

3 HydrochlorideM.p.: 116° C. 94

2 OxalateM.p.: 71° C.(amorphous powder) 95

3 BaseM.p.: 94° C. 96

5 OxalateM.p.: 120° C. 97

4 OxalateM.p.: 121° C. 98

3 HydrochlorideM.p.: 129° C. 99

3 Oxalate(amorphous whitesolid) 100

3 HydrochlorideM.p.: 158° C. 101 —NH—C₄H₉-n 2 OxalateM.p.: 188° C. 102—NH—C₄H₉-n 3 OxalateM.p.: 170° C. 103 —N(C₄H₉-n)₂ 2 Oxalate(amorphouswhitesolid) 104

2 OxalateM.p.: 86° C. 105

2 HydrochlorideM.p.: 89° C. 106

3 HydrochlorideM.p.: 179° C. 107

3 OxalateM.p.: 150° C. 108

2 HydrochlorideM.p.: 156° C. 109

3 OxalateM.p.: 127° C. 110

3 HydrochlorideM.p.: 86° C. 111

3 HydrochlorideM.p.: 161° C. 112

3 HydrochlorideM.p.: 172° C. 113

3 HydrochlorideM.p.: 146° C. 114

3 HydrochlorideM.p.: 154° C. 115

3 HydrochlorideM.p.: 117° C. 116

3 Hydrochloride(solid) 117

Am′ n′ Characteristics Ex.

3 Base(amorphous solid) 118

3 Base M.p.: 108° C. 119

2 Base M.p.: 80° C. 120

2 Base(amorphous white solid) 121

2 Base(amorphous white solid) 122

3 Base(amorphous white solid) 123

2 Hydrochloride(solid) 124

3 Base M.p.: 95° C. 125

2 Base(amorphous solid) 126

3 Base(amorphous solid) 127 —N(C₂H₅)₂ 2 Base M.p.: 73° C. 128

3 TrihydrochlorideM.p.: >200° C.(degradation) 129

3 HydrochlorideM.p.: 156° C. 130

3 Base(amorphous powder) 131

3 HydrochlorideM.p.: 106° C. 132

3 HydrochlorideM.p.: 116° C. 133

3 Base M.p.: 85° C. 134

5 Base M.p.: 167° C. 135

2 HydrochlorideM.p.: 173° C. 136

4 Base M.p.: 100° C. 137

3 Hydrochloride(solid) 138

3 HydrochlorideM.p.: 191° C. 139

3 Hydrochloride(amorphous powder) 140

2 Hydrochloride(solid) 141 —N(C₄H₉)₂ 2 Base 142 (amorphous solid)—N(C₄H₉)₂ 3 Hydrochloride 143 (amorphous powder)

3 Hydrochloride(amorphous powder) 144 —N(C₂H₅)₂ 3 Base M.p.: 83° C. 145

2 HydrochlorideM.p.: 188–190° C. 146 —NH—C₅H₉-neo 3 Base M.p.: 188° C.147

2 Base(amorphous solid) 148

The compounds listed below were also prepared.

Compound Characteristics Example

Oxalate SolidM.p.: 130° C. 152

Oil 153

Oxalate Ice(NMR spectrum below) 154

Oxalate PowderM.p.: 87–88° C. 155

Hydrochloride SolidM.p.: 140–142° C. 160

Hydrochloride SolidM.p.: 141–143° C. 161

EXAMPLE 149

A capsule containing the following ingredients was prepared according toknown pharmaceutical techniques:

Ingredient Mg Compound of the invention 100.0 Starch 99.5 Colloidalsilica 0.5

¹H NMR Spectra at 200 MHz EXAMPLE 153

Solvent: DMSO

δ (ppm): 6.9–8.2 (unresolved peak, 7H); 4.85 (broad singlet, 1H);3.7–4.3 (unresolved peak, 6H); 2.2–3.0 (unresolved peak, 8H); 0.6–1.8(unresolved peak, 21H)

EXAMPLE 154

Solvent: DMSO

δ (ppm): 6.7–7.5 (unresolved peak, 7H); 4.45 (singlet, 2H); 3.7–4.3(unresolved peak, 6H); 3.2–3.5 (unresolved peak, 2H); 2.95 (broad doubledoublet, 4H); 2.80 (triplet, 2H); 0.7–3.3 (unresolved peak, 21H)

EXAMPLE 158

Solvent: DMSO

δ (ppm): 6.9–8.2 (unresolved peak, 7H); 2.6–4.8 (unresolved peak, 16H);0.9–2.3 (unresolved peak, 18H); 0.78 (triplet, 3H)

EXAMPLE 162

Solvent: DMSO

δ (ppm): 6.9–8.2 (unresolved peak, 7H); 3.0–4.4 (unresolved peak, 8H);2.80 (triplet, 2H); 1.0–2.3 (unresolved peak, 10H); 0.78 (triplet, 3H)

1. Benzofuran or benzothiophene compounds of general formula:

and also their pharmaceutically acceptable salts, in which formula: Arepresents —O—, —S— or

B represents a linear or branched C₁–C₅ alkylene group optionallysubstituted with a hydroxyl group, T represents hydrogen or a C₁–C₄alkyl radical R represents the cyano or hydroxymethyl group an oximegroup of formula:R₄—O—N═CH— in which R₄ represents a C₁–C₄ alkyl group a carboxyl groupof general formula:

in which R₅ represents hydrogen or an alkali metal atom, a linear orbranched C₁–C₁₀ alkyl group or a C₃–C₆ cycloalkyl group, or R₅represents the group of general formula:

in which r represents 1 to 4 a carboxyl group of general formula:

in which R′₅ represents a piperidinyl group optionally N-substitutedwith a C₁–C₄ alkyl group or one of the groups of general formula:

in which R₆ and R₇, which may be identical or different, represent aC₁–C₄ alkyl group, R₈ represents a linear or branched C₁–C₆ alkylenegroup, and R₉ represents hydrogen, an alkali metal atom or a C₁–C₄ alkylgroup, an aminocarbonyl group of formula:

in which R₁₀ represents hydrogen, a C₁–C₄ alkyl, hydroxyl or aminogroup, a group (c) above or one of the groups:

in which R₁₁ represents a group (a) and R₁₂ represents a C₁–C₆ alkyleneradical, a group of formula:

in which R₁₃ and R₁₄, which may be identical or different, represent aC₁–C₄ alkyl radical or a C₁–C₄ hydroxyalkyl group, one of the groups offormula below:

R₁ represents a C₁–C₆ alkyl, or a group of formula:—(CH₂)_(p)—R₁₁  (m) in which R₁₁ has the same meaning as previously andp represents 1 to 4, Am represents a nitrogenous group of formula:

in which: R₂ represents hydrogen, a linear or branched C₁–C₆ alkyl groupoptionally substituted with a hydroxyl group, a group (m), a C₃–C₆cycloalkyl group or a benzyl group, R₃ represents a linear or branchedC₁–C₆ alkyl group optionally substituted with a hydroxyl group, a C₃–C₆cycloalkyl group, a group (m), a benzyl group or a phenyl group offormula:

R₁₆, R₁₇ and R₁₈, which may be identical or different, representhydrogen, or a hydroxyl, nitro, amino, C₁–C₄ alkoxy or C₁–C₄alkylsulfonamido group, m in represents 0 or 1, R₂ and R₃, when they oretaken together, represent a linear or branched C₃–C₁₀ alkylene groupoptionally substituted with the hydroxyl group, with a group (a) or witha group (m) and optionally interrupted by —O—, W, W′ and Z are suchthat: when W and W′, which are identical, represent CH, Z represents —O—or —S—, when W represents CH and W′ represents C—R₂₀, Z represents

R₂₀ and R₂₁ being identical or different and representing hydrogen, ahalogen atom, a C₁–C₄ alkyl radical, or a C₁–C₄ alkoxy radical, Xrepresents —O— or —S—, Y represents a —CO— or —CH₂— radical, or aradical of formula

in which R₂₂ represents hydrogen, a C₁–C₄ alkyl radical or an acylradical of formula:

in which R₂₃ represents a C₁–C₄ alkyl radical, or Y represents

it being understood that the combination of the R, R₁ and Am groupscontains 0, 1 or 2 groups (a), these benzofuran or benzothiophenederivatives being in the form of individual isomers or of a mixturethereof, thereof.
 2. Benzofuran or benzothiophene derivatives accordingto claim 1, in which R represents the isopropoxycarbonyl group. 3.Benzofuran or benzothiophene derivatives according to claim 2, in whichAm represents a diethylpiperidinyl group.
 4. Benzofuran orbenzothiophene derivatives according to claim 3, in which Y representsthe —CO— radical.
 5. Benzofuran or benzothiophene derivatives accordingto claim 4, in which

represents the benzoyl radical.
 6. Benzofuran or benzothiophenederivatives according to claim 5, in which:

represents the 4-oxybenzoyl radical.
 7. Benzofuran or benzothiophenederivatives according to claim 6, in which the chain:A-B-Am is located at position
 4. 8. Benzofuran or benzothiophenederivatives according to claim 7, in which R₁ represents n-butyl, Brepresents the propylene group and Am represents a diethylpiperidinylgroup.
 9. Benzofuran or benzothiophene derivatives according to claim 8,in which the diethylpiperidinyl group is the 3,5-diethylpiperidinylgroup.
 10. Benzofuran or benzothiophene derivatives according to claim1, in which the pharmaceutically acceptable salt is chosen from oxalate,maleate, fumarate, methanesulfonate, benzoate, ascorbate, pamoate,succinate, hexamate, bismethylenesalicylate, ethanedisulfonate, acetate,propionate, tartrate, salicylate, citrate, gluconate, lactate, malate,cinnamate, aspartate, palmitate, stearate, itaconate, glycolate,p-aminobenzoate, glutamate, benzenesulfonate, p-toluenesulfonate andtheophyllineacetate salts and the salts formed from an amino acid. 11.Benzofuran or benzothiophene compounds according to claim 1 in which thepharmaceutically acceptable salt is chosen from the hydrochloride,hydrobromide, sulfate, sulfamate, phosphate and nitrate salts. 12.Benzofuran or benzothiophene compounds according to claim 9 in which thepharmaceutically acceptable salt is chosen from oxalate, maleate,fumarate, methanesulfonate, benzoate, ascorbate, pamoate, succinate,hexamate, bismethylenesalicylate, ethanedisulfonate, acetate,propionate, tartrate, salicylate, citrate, gluconate, lactate, malate,cinnamate, mandelate, citraconate, aspartate, palmitate, stearate,itaconate, glycolate, p-aminobenzoate, glutamate, benzenesulfonate,p-toluenesulfonate and theophyllineacetate salts and the salts formedfrom an amino acid.
 13. Benzofuran or benzothiophene compounds accordingto claim 9 in which the pharmaceutically acceptable salt is chosen fromhydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitratesalts.
 14. Benzofuran or benzothiophene compounds according to claim 10in which the salt formed from an amino acid is a lysine or histidinesalt.
 15. Benzofuran or benzothiophene compounds according to claim 12in which the salt formed from an amino acid is a lysine or histidinesalt.
 16. Process for the preparation of benzofuran or benzothiophenederivatives according to claim 1, in which Y represents the —CO— group,R₁ and (Am₁) comprise no carboxylic or alkali metal carboxylate group,R₁₆ and/or R₁₇ and/or R₁₈ are different from the amino group or from aC₁–C₄ alkylsulfonamido group and R represents a cyano or hydroxymethylgroup, the group (k) or a group (a) in which R₅ represents a C₁–C₁₀alkyl or C₃–C₆ cycloalkyl group, wherein a ketone compound of generalformula:

in which R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl orbenzyl group or a group (m) comprising no carboxylic or alkali metalcarboxylate group, T, W, W′, X and Z have the same meaning as in claim1, A′ represents OH, SH or NH₂ and R′ represents a cyano orhydroxymethyl group, the group (k) or a —CO₂R″₅ group in which R″₅represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, is reacted, inthe presence of a basic agent, with a compound of general formula:R₂₄-B-Am′  (3) in which Am′ represents a group (Am₁) as defined in claim1, this group comprising no carboxylic or alkali metal carboxylategroup, —R₁₆ and/or R₁₇ and/or R₁₈ are different from an amino group or aC₁–C₄ alkylsulfonamido group, B has the same meaning as in claim 1 andR₂₄ represents: either a halogen atom, or a C₁–C₄ alkylsulfonyloxy orC₆–C₁₀arylsulfonyloxy radical, which makes it possible to obtain, in thefree base form, the desired compounds in which A represents —O— or —S—,or a halocarbonyl group, which makes it possible to obtain, in the freebase form, the desired compounds in which A represents —NH—CO—, thecompounds in the free base form thus obtained possibly being, ifnecessary, treated with a suitable organic or inorganic acid, to form apharmaceutically acceptable salt.
 17. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ and (Am₂) comprise no carboxylic oralkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are differentfrom the amino group or from a C₁–C₄ alkylsulfonamido group and Rrepresents the cyano group, the group (k), an R₄—O—N═CH— group or agroup (a) in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkylgroup, wherein a compound of general formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R₁₁ represents a C₁–C₆ alkyl group, a C₃–C₆ cycloalkyl, phenyl or benzylgroup or a group (m) comprising no carboxylic or alkali metalcarboxylate group and R″ represents the cyano group, the group (k), anR₄—O—N═CH— group or a —CO₂R″₅ group in which R″₅ represents a C₁–C₁₀alkyl or C₃–C₆ cycloalkyl group and Hal represents a halogen atom, isreacted with a compound of general formula:H-Am′  (5) optionally in the form of a salt, in which Am′ represents agroup (Am₁) or (Am₂) as defined in claim 1, this group comprising nocarboxylic or alkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈are different from an amino group or a C₁–C₄ alkylsulfonamido group, thereaction taking place in the presence of a basic agent or an excess ofamine of formula (5) in the basic form, which gives the desiredcompounds in the free base form, which base can be reacted, ifnecessary, with a suitable organic or inorganic acid, to form apharmaceutically acceptable salt.
 18. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ and (Am₁) comprise no carboxylic oralkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are differentfrom the amino group or from a C₁–C₄ alkylsulfonamido group and Rrepresents the cyano group, an R₄—O—N═CH— group, a group (a) in which R₅represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group or else the group(k), wherein a compound of general formula:

in which T and X have the same meaning as in claim 1, R″ represents thecyano group, the group (k), an R₄—O—N═CH— group or a —CO₂R″₅ group inwhich R″₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group and R′₁represents a C₁–C₆ alkyl group, a C₃–C₆ cycloalkyl, phenyl or benzylgroup or a group (m) comprising no carboxylic or alkali metalcarboxylate group, is reacted with a halide of general formula:

in which A, B, W, W′ and Z have the same meaning as in claim 1, Halrepresents a halogen atom and Am′ represents a group (Am₁) as defined inclaim 1, this group comprising no carboxylic or alkali metal carboxylategroup, R₁₆ and/or R₁₇ and/or R₁₈ are different from an amino group or aC₁–C₄ alkylsulfonamido group, the reaction optionally taking place inthe presence of a Lewis acid, which gives the desired compounds in thefree base form, which base can be reacted, if necessary, with an organicor inorganic acid, to form a pharmaceutically acceptable salt. 19.Process for the preparation of benzofuran or benzothiophene derivativesaccording to claim 1, in which Y represents the —CO— group, R₁ and (Am₁)comprise no carboxylic or alkali metal carboxylate group, R₁₆ and/or R₁₇and/or R₁₈ are different from the amino group or from a C₁–C₄alkylsulfonamido group and R represents the group (j), wherein acompound of formula:

in which A, B, T, W, W′, X and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, is reacted with phosgene, which gives thedesired compounds in the hydrochloride form, which hydrochloride can betreated, if necessary, with a basic agent, such as an alkali metalhydroxide or an alkali metal carbonate, which gives the desiredcompounds in the free base form, which base can be reacted, ifnecessary, with an organic or inorganic acid, to form a pharmaceuticallyacceptable salt.
 20. Process for the preparation of benzofuran orbenzothiophene derivatives according to claim 1, in which Y representsthe —CO— group, R₁ and (Am₁) comprise no carboxylic or alkali metalcarboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are different from theamino group or from a C₁–C₄ alkylsulfonamido group and R represents agroup (b) in which R′₅ represents a group (c) of the primarydialkylaminoalkyl type, wherein a compound of formula:

in which A, B, T, X, W, W′, X and Z have the same meaning as in claim 1,R₁₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amino functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with an alcohol of general formula:

in which R₆ and R₇ have the same meaning as in claim 1 and R₈ representsa linear C₁–C₈ alkylene group, the reaction taking place in the presenceof carbonyldiimidazole and 1,8-diazabicyclo[5.4.0]undec-7-ene, and then,if necessary, the compound formed is deprotected, which gives thedesired compounds in the free base form, which base can be treated, ifnecessary, with a suitable organic or inorganic acid, to produce apharmaceutically acceptable salt.
 21. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ and (Am₁) comprise no carboxylic oralkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are differentfrom the amino group or from a C₁–C₄ alkylsulfonamido group and Rrepresents a group (b) in which R′₅ represents a group (c) of thesecondary or tertiary dialkylaminoalkyl type, wherein a compound offormula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amino functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a halogenating agent, to produce an acyl halide, which issubsequently treated with an alcohol of formula:

in which R₆ and R₇ have the same meaning as in claim 1 and R₈ representsa secondary or tertiary C₂–C₆ alkylene group, and then, if necessary,the compound formed is deprotected, which gives the desired compounds inthe hydrohalide form or in the free base form when the compound offormula (10) is in excess, which hydrohalide can be treated, ifnecessary, with a basic agent, such as an alkali metal hydroxide or analkali metal carbonate, to produce the desired compounds in the freebase form, the free base thus formed possibly being, if necessary,treated with a suitable organic or inorganic acid, to produce apharmaceutically acceptable salt.
 22. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ and (Am₁) comprise no carboxylic oralkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are differentfrom the amino group or from a C₁–C₄ alkylsulfonamido group and Rrepresents either a group (a) in which R₅ represents a C₁–C₁₀ alkyl orC₃–C₆ cycloalkyl group, or a group (b) in which R′₅ represents apiperidinyl group optionally N-substituted with a C₁–C₄ alkyl group orin which R′₅ represents a group (d) comprising no carboxylic or alkalimetal carboxylate group, wherein a compound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amino functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a halogenating agent, to produce an acyl halide, which issubsequently treated with an alcohol of general formula:R′″₅—OH  (12) in which R′″₅ represents a C₁–C₁₀ alkyl or C₃–C₆cycloalkyl group or a group (b) in which R′₅ represents a piperidinylgroup optionally N-substituted with a C₁–C₄ alkyl group or R′₅represents a group (d) comprising no carboxylic or alkali metalcarboxylate group, and then, if necessary, the compound formed isdeprotected, which gives the desired compounds in the hydrohalide formor in the free base form when the compound of formula (10) is in excess,which hydrohalide can be treated, if desired, with a basic agent, suchas an alkali metal hydroxide or an alkali metal carbonate, to producethe desired compounds in the free base form, the free base thus formedpossibly being, if necessary, treated with a suitable organic orinorganic acid, to produce a pharmaceutically acceptable salt. 23.Process for the preparation of benzofuran or benzothiophene derivativesaccording to claim 1, in which Y represents the —CO— group, R₁ and (Am₁)comprise no carboxylic or alkali metal carboxylate group, R₁₆ and/or R₁₇and/or R₁₈ are different from the amino group or from a C₁–C₄alkylsulfonamido group and R represents a group (e) in which R₁₀represents a group (f) comprising no carboxylic or alkali metalcarboxylate group, wherein a compound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amine functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a halogenating agent, to produce an acyl chloride, which issubsequently treated with a compound of formula:

in which R″₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, andthen, if necessary, the compound formed is deprotected, which gives, inthe free base form, the desired compounds in which R₁₀ represents agroup (f) in which the R₁₁ group represents a group (a) in which R₅represents a C₁–C₄ alkyl or C₃–C₆ cycloalkyl group, the free base thusformed possibly being, if necessary, treated with a suitable organic orinorganic acid, to form a pharmaceutically acceptable salt.
 24. Processfor the preparation of benzofuran or benzothiophene derivativesaccording to claim 1, in which Y represents the —CO— group, R₁ and (Am₁)comprise no carboxylic or alkali metal carboxylate group, R₁₆ and/or R₁₇and/or R₁₈ are different from the amino group or from a C₁–C₄alkylsulfonamido group and R represents a group (e) in which R₁₀represents a C₁–C₄ alkyl group, an amino group or a group (c), wherein acompound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amine functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a halogenating agent, to produce an acyl halide, which issubsequently treated with an amine of general formula:R₁₀—NH₂  (14)or

in which R₆, R₇ and R₈ have the same meaning as in claim 1 and R′₁₀represents a C₁–C₄ alkyl or amino radical, and then, if necessary, thecompound formed is deprotected, which gives, optionally after basictreatment, the desired compound of formula (1) in the hydrohalide formor in the free base form when the compound of formula (10) is in excess,which hydrohalide can be treated, if necessary, with a basic agent, suchas an alkali metal hydroxide or an alkali metal carbonate, to producethe desired compounds in the free base form, which base can, ifnecessary, be reacted with a suitable organic or inorganic acid, to forma pharmaceutically acceptable salt.
 25. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ and (Am₁) comprise no carboxylic oralkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are differentfrom the amino group or from a C₁–C₄ alkylsulfonamido group and Rrepresents a group (e) in which R₁₀ represents a group (g) comprising nocarboxylic or alkali metal carboxylate group, wherein a compound offormula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amine functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a salt of a compound of general formula:

in which R₁₂ has the same meaning as in claim 1 and R′₁₁ represents aC₁–C₄ alkyl or C₃–C₆ cycloalkyl radical, the reaction taking place inthe presence of an acid scavenger, and then, if necessary, the compoundformed is deprotected, which gives, in the free base form, the desiredcompounds in which R₁₀ represents a group (g) in which the R₁₁ grouprepresents a group (a) in which R₅ represents a C₁–C₄ alkyl or C₃–C₆cycloalkyl group, the free base thus formed possibly being, ifnecessary, treated with a suitable organic or inorganic acid, to producea pharmaceutically acceptable salt.
 26. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ and (Am₁) comprise no carboxylic oralkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ are differentfrom the amino group or from a C₁–C₄ alkylsulfonamido group and Rrepresents a group (h), wherein a compound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amine functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a halogenating agent, to produce an acyl halide, which issubsequently treated with an amine of general formula:

in which R₁₃ and R₁₄ have the same meaning as in claim 1, and then, ifnecessary, the compound formed is deprotected, which gives a salt of thedesired compound, which is treated with a suitable basic agent, toproduce, in the free base form, the desired compounds, the free basethus formed possibly being, if necessary, treated with an organic orinorganic acid, to produce a pharmaceutically acceptable salt. 27.Process for the preparation of benzofuran or benzothiophene derivativesaccording to claim 1, in which Y represents the —CO— group, R₁ and (Am₁)comprise no carboxylic or alkali metal carboxylate group, R₁₆ and/or R₁₇and/or R₁₈ are different from the amino group or from a C₁–C₄alkylsulfonamido group and R represents a group (e) in which R₁₀represents the hydroxyl group, wherein a compound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1, R′1 represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl group ora group (m) comprising no carboxylic or alkali metal carboxylate groupand Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, after protection of the amine functional groupwhen Am′ represents a group (Am₁) in which R₂ represents hydrogen, isreacted with a benzyloxyamine salt, in the presence of an acid scavengerand of benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate, and then, if necessary, the compound formed isdeprotected, which gives benzyloxyaminocarbonyl derivatives, which arehydrogenated in the presence of a suitable catalyst, to produce, in thefree base form, the desired compounds, which are treated, if necessary,with a suitable organic or inorganic acid, to form a pharmaceuticallyacceptable salt.
 28. Process according to one of claims 21 wherein theprotection of the amine functional group is carried out by treatment bymeans of 9-fluorenylmethyl chloroformate and the deprotection is carriedout by treatment with a secondary amine.
 29. Process for the preparationof benzofuran or benzothiophene derivatives according to claim 1, inwhich Y represents the —CO— group, R₁ and (Am₁) comprise no carboxylicor alkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ aredifferent from the amino group or from a C₁–C₄ alkylsulfonamido groupand R represents a group (e) in which R₁₀ represents hydrogen, wherein acompound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, is hydrolyzed in the presence of a strong acid,which gives the desired compounds in the free base form, which base canbe treated, if necessary, with a suitable organic or inorganic acid, toform a pharmaceutically acceptable salt.
 30. Process for the preparationof benzofuran or benzothiophene derivatives according to claim 1, inwhich Y represents the —CO— group, R₁ and (Am₁) comprise no carboxylicor alkali metal carboxylate group, R₁₆ and/or R₁₇ and/or R₁₈ aredifferent from the amino group or from a C₁–C₄ alkylsulfonamido groupand R represents the group (1), wherein a compound of formula:

in which A, B, T, X, W, W′ and Z have the same meaning as in claim 1,R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl, phenyl or benzyl groupor a group (m) comprising no carboxylic or alkali metal carboxylategroup and Am′ represents a group (Am₁) as defined in claim 1, this groupcomprising no carboxylic or alkali metal carboxylate group, R₁₆ and/orR₁₇ and/or R₁₈ are different from an amino group or a C₁–C₄alkylsulfonamido group, is reacted with tributylazidotin, which givesthe desired compounds in the free base form, which base can be treated,if necessary, with a suitable organic or inorganic acid, to form apharmaceutically acceptable salt.
 31. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents the —CO— group, R₁ comprises no carboxylic or alkali metalcarboxylate group and Am represents a group (Am₁) comprising nocarboxylic or alkali metal carboxylate group and in which R₁₆ and/or R₁₇and/or R₁₈ represent the amino group, wherein a nitro compound offormula:

in which A, B, T, W, W′, X and Z have the same meaning as in claim 1, Rhas the same meaning as in claim 1 but comprises no carboxylic or alkalimetal carboxylate group, R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl,phenyl or benzyl group or a group (m) comprising no carboxylic or alkalimetal carboxylate group and Am′₁ represents either a group (Am₁)comprising no carboxylic or alkali metal carboxylate group and in whichR₁₆ and/or R₁₇ and/or R₁₈ represent the nitro group, is hydrogenated inthe presence of a suitable catalyst, which gives, in the free base form,the desired compounds, which can be reacted, if necessary, with asuitable organic or inorganic acid, to form a pharmaceuticallyacceptable salt.
 32. Process for the preparation of benzofuran orbenzothiophene derivatives according to claim 1, in which Y representsthe —CO— group, R₁ comprises no carboxylic or alkali metal carboxylategroup and Am represents a group (Am₁) comprising no carboxylic or alkalimetal carboxylate group and in which R₁₆ and/or R₁₇ and/or R₁₈ representa C₁–C₄ alkylsulfonamido group, wherein an amino compound of formula:

in which A, B, T, W, W′, X and Z have the same meaning as in claim 1, Rhas the same meaning as in claim 1 but comprises no carboxylic or alkalimetal carboxylate group, R′₁ represents a C₁–C₆ alkyl, C₃–C₆ cycloalkyl,phenyl or benzyl group or a group (m) comprising no carboxylic or alkalimetal carboxylate group and Am′₂ represents either a group (Am₁)comprising no carboxylic or alkali metal carboxylate group and in whichR₁₆ and/or R₁₇ and/or R₁₈ represent the amino group, is reacted with ahalide of general formula:Hal-SO₂—R′₁₆  (21) or an anhydride of general formula:(R′₁₆SO₂)₂O  (22) in which R′₁₆ represents a linear or branched C₁–C₄alkyl radical, optionally in the presence of an acid acceptor, whichgives, in the free base form, the desired compounds, which can bereacted, if necessary, with a suitable organic or inorganic acid, toform a pharmaceutically acceptable salt.
 33. Process for the preparationof benzofuran or benzothiophene derivatives according to claim 1, inwhich Y represents the —CO— group and one or two of the groups R, R₁,and (Am₁) comprise a —CO₂R₅ group in which R₅ represents hydrogen or analkali metal atom, the other group(s) being different from a —CO₂R₅group in which R₅ represents a C₁–C₁₀alkyl or C₃–C₆ cycloalkyl radical,wherein a compound of formula:

in which A, B, R, R₁, T, W, W′, X and Z have the same meaning as inclaim 1, Am′₃ represents a group (Am₁) as defined in claim 1, and R, R₁,and (Am₁) are such that one or two of them comprise(s) a —CO₂R″₅ groupin which R″₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, theother group(s) being different from a —CO₂R₅ group in which R₅represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, is saponified inthe presence of an alkali metal hydroxide, which gives, in the free baseform, the desired compounds of formula (1) in which one or two of thegroups R, R₁, and (Am₁) comprise(s) a —CO₂R₅ group in which R₅represents an alkali metal atom, which compound can be treated, ifnecessary, with a strong acid, which gives, in the free base form, thedesired compounds of formula (1) in which R₅ represents hydrogen, thefree bases thus formed possibly being, if necessary, treated with asuitable organic or inorganic acid, to produce a pharmaceuticallyacceptable salt.
 34. Process for the preparation of benzofuran orbenzothiophene derivatives according to claim 1, in which Y representsthe —CO— group and one of two of the groups R, R₁, and (Am₁) comprises a—CO₂R₅ group in which R₅ represents hydrogen or an alkali metal atom,and the other comprises a —CO₂R₅ group in which R₅ represents a C₁–C₁₀alkyl or C₃–C₆ cycloalkyl group, the third group being different from a—CO₂R₅ group in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkylgroup, wherein: a compound of formula:

 in which A, B, R, R₁, T, W, W′, X and Z have the same meaning as inclaim 1, Am′₄ represents a group (Am₁) as defined in claim 1, and R, R₁,and (Am₁) are such that one of them comprises a —CO₂R″₅ group in whichR″₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group and another ofthem comprises a benzyloxycarbonyl group, the third group beingdifferent from a —CO₂R₅ group in which R₅ represents a C₁–C₁₀ alkyl orC₃–C₆ cycloalkyl group, is hydrogenated in the presence of a suitablecatalyst; a compound of formula:

 in which A, B, R, R₁, T, W, W′, X and Z have the same meaning as inclaim 1, Am′₅ represents a group (Am₁) as defined in claim 1, and R, R₁,and (Am₁) are such that one of them comprises a —CO₂R″₅ group in whichR″₅ has the same meaning as above and another of them comprises at-butoxycarbonyl group, the third group being different from a —CO₂R₅group in which R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group,is hydrolyzed in the presence of trifluoroacetic acid, which makes itpossible to produce the desired compounds of formula (1) in which one oftwo of the groups R, R₁, and (Am₁) comprises a —CO₂R₅ group in which R₅represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group, and the othercomprises a —CO₂R₅ group in which R₅ represents hydrogen, whichcompounds can be treated, if necessary, with a suitable basic agent, toproduce, in the free base form, the desired compounds of formula (1) inwhich one of two of the groups R, R₁, and (Am₁) comprises a —CO₂R₅ groupin which R₅ represents an alkali metal atom, the other a —CO₂R₅ group inwhich R₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl group, whichcompounds can themselves be treated, if necessary, with a strong acid,to produce, in the free base form, the desired compounds of formula (1)in which one of two of the groups R, R₁, (Am₁) comprises a carboxylicgroup, the other a —CO₂R₅ group in which R₅ represents a C₁–C₁₀ alkyl orC₃–C₆ cycloalkyl group, the free bases thus formed possibly being, ifnecessary, treated with a suitable organic or inorganic acid, to producea pharmaceutically acceptable salt.
 35. Process for the preparation ofbenzofuran or benzothiophene derivatives according to claim 1, in whichY represents —CO—, R represents the cyano group and one of the groups R₁or (Am₁) comprises a carboxylic group, wherein a compound of formula (1)according to claim 1, in which Y represents the —CO— group, R representsthe cyano group, and in which A, B, R₁, T, W, W′, X and Z have the samemeaning as in claim 1, Am represents a group (Am₁) as defined in claim 1and R₁ and (Am₁) are such that one of them comprises a —CO₂R″₅ group inwhich R″₅ represents a C₁–C₁₀ alkyl or C₃–C₆ cycloalkyl radical, istreated by means of tributyltin oxide, to produce the desired compoundsin the free base form, which base can be reacted, if necessary, with anorganic or inorganic acid, to form a pharmaceutically acceptable salt.36. Process for the preparation of benzofuran or benzothiophenederivatives according to claim 1, in which Y represents the group

characterized in that a compound of formula (1) according to claim 1, inwhich Y represents the —CO— group and in which A, B, Am, R, R₁, T, W,W′, X and Z have the same meaning as in claim 1, is reduced by means ofan alkali metal borohydride, which gives the desired compounds in thefree base form, which base can be reacted, if necessary, with an organicor inorganic acid, to produce a pharmaceutically acceptable salt. 37.Process for the preparation of benzofuran or benzothiophene derivativesaccording to claim 1, in which Y represents the group

in which R₂₂ represents a C₁–C₄ alkyl radical wherein a compound offormula (1) according to claim 1, in which Y represents the —CHOH— groupand in which A, B, Am, R, R₁, T, W, W′, X and Z have the same meaning asin claim 1, is reacted with an alkali metal alkoxide and then with ahalide of formula:R₂₃-Hal in which Hal represents a halogen atom and R₂₃ represents aC₁–C₄ alkyl radical, which gives the desired compounds in the free baseform, which base can be reacted, if necessary, with an organic orinorganic acid, to produce a pharmaceutically acceptable salt. 38.Process for the preparation of benzofuran or benzothiophene derivativesaccording to claim 1, in which Y represents a group

in which R₂₂ represents an acyl radical of formula —CO—R₂₃ in which R₂₃represents a C₁–C₄ alkyl radical, wherein a compound of formula (1)according to claim 1, in which Y represents the —CHOH— group and inwhich A, B, Am, R, R₁, T, W, W′, X and Z have the same meaning as inclaim 1, is reacted with an acyl halide of formula:

in which Hal represents a halogen atom and R₂₃ represents a C₁–C₄ alkylradical, which gives the desired compounds in the free base form, whichbase can be reacted, if necessary, with an organic or inorganic acid, toform a pharmaceutically acceptable salt.
 39. Process for the preparationof benzofuran or benzothiophene derivatives according to claim 1, inwhich Y represents the —CH₂— group, wherein a compound of formula (1)according to claim 1, in which Y represents the —CHOH— group and inwhich A, B, Am, R, R₁, T, W, W′, X and Z have the same meaning as inclaim 1, is reduced by means of an alkali metal borohydride, in thepresence of trifluoroacetic acid, which gives the desired compounds inthe free base form, which base can be reacted, if necessary, with asuitable organic or inorganic acid, to form a pharmaceuticallyacceptable salt.
 40. A process according to claim 22 wherein theprotection of the amine functional group is carried out by treatment bymeans of 9-fluorenylmethyl chloroformate and the deprotection is carriedout by treatment with a secondary amine.
 41. A process according toclaim 23 wherein the protection of the amine functional group is carriedout by treatment by means of 9-fluorenylmethyl chloroformate and thedeprotection is carried out by treatment with a secondary amine.
 42. Aprocess according to claim 24 wherein the protection of the aminefunctional group is carried out by treatment by means of9-fluorenylmethyl chloroformate and the deprotection is carried out bytreatment with a secondary amine.
 43. A process according to claim 25wherein the protection of the amine functional group is carried out bytreatment by means of 9-fluorenylmethyl chloroformate and thedeprotection is carried out by treatment with a secondary amine.
 44. Aprocess according to claim 26 wherein the protection of the aminefunctional group is carried out by treatment by means of9-fluorenylmethyl chloroformate and the deprotection is carried out bytreatment with a secondary amine.
 45. A process according to claim 27wherein the protection of the amine functional group is carried out bytreatment by means of 9-fluorenylmethyl chloroformate and thedeprotection is carried out by treatment with a secondary amine.
 46. Apharmaceutical or veterinary composition comprising as active principle,a therapeutically effective amount of at least one benzofuran orbenzothiophene compound, or a pharmaceutically acceptable salt thereof,according to claim 1 in combination with a suitable excipient orpharmaceutical vehicle.
 47. A pharmaceutical or veterinary compositionaccording to claim 46 comprising from 50 to 500 mg of active principle.48. A pharmaceutical or veterinary composition comprising as activeprinciple, a therapeutically effective amount of at least one benzofuranor benzothiophene compound, or a pharmaceutically acceptable saltthereof, according to claim 2 in combination with a suitable excipientor pharmaceutical vehicle.
 49. A pharmaceutical or veterinarycomposition comprising as active principle, a therapeutically effectiveamount of at least one benzofuran or benzothiophene compound, or apharmaceutically acceptable salt thereof, according to claim 3 incombination with a suitable excipient or pharmaceutical vehicle.
 50. Apharmaceutical or veterinary composition comprising as active principle,a therapeutically effective amount of at least one benzofuran orbenzothiophene compound, or a pharmaceutically acceptable salt thereof,according to claim 4 in combination with a suitable excipient orpharmaceutical vehicle.
 51. A pharmaceutical or veterinary compositioncomprising as active principle, a therapeutically effective amount of atleast one beuzofuran or benzothiophene compound, or a pharmaceuticallyacceptable salt thereof, according to claim 5 in combination with asuitable excipient or pharmaceutical vehicle.
 52. A pharmaceutical orveterinary composition comprising as active principle, a therapeuticallyeffective amount of at least one beuzofuran or benzothiophene compound,or a pharmaceutically acceptable salt thereof, according to claim 6 incombination with a suitable excipient or pharmaceutical vehicle.
 53. Apharmaceutical or veterinary composition comprising as active principle,a therapeutically effective amount of at least one beuzofuran orbenzothiophene compound, or a pharmaceutically acceptable salt thereof,according to claim 7 in combination with a suitable excipient orpharmaceutical vehicle.
 54. A pharmaceutical or veterinary compositioncomprising as active principle, a therapeutically effective amount of atleast one beuzofuran or benzothiophene compound, or a pharmaceuticallyacceptable salt thereof, according to claim 8 in combination with asuitable excipient or pharmaceutical vehicle.
 55. A pharmaceutical orveterinary composition comprising as active principle, a therapeuticallyeffective amount of at least one benzofuran or benzothiophene compound,or a pharmaceutically acceptable salt thereof, according to claim 9 incombination with a suitable excipient or pharmaceutical vehicle.
 56. Apharmaceutical or veterinary composition comprising as active principle,a therapeutically effective amount of at least one beuzofuran orbenzothiophene compound, or a pharmaceutically acceptable salt thereof,according to claim 10 in combination with a suitable excipient orpharmaceutical vehicle.
 57. A pharmaceutical or veterinary compositioncomprising as active principle, a therapeutically effective amount of atleast one benzofuran or benzothiophene compound, or a pharmaceuticallyacceptable salt thereof, according to claim 11 in combination with asuitable excipient or pharmaceutical vehicle.
 58. A pharmaceutical orveterinary composition comprising as active principle, a therapeuticallyeffective amount of at least one benzofuran or benzothiophene compound,or a pharmaceutically acceptable salt thereof, according to claim 12 incombination with a suitable excipient or pharmaceutical vehicle.
 59. Apharmaceutical or veterinary composition comprising as active principle,a therapeutically effective amount of at least one benzofuran orbenzothiophene compound, or a pharmaceutically acceptable salt thereof,according to claim 13 in combination with a suitable excipient orpharmaceutical vehicle.
 60. A pharmaceutical or veterinary compositioncomprising as active principle, a therapeutically effective amount of atleast one benzofuran or benzothiophene compound, or a pharmaceuticallyacceptable salt thereof, according to claim 14 in combination with asuitable excipient or pharmaceutical vehicle.
 61. A pharmaceutical orveterinary composition comprising as active principle, a therapeuticallyeffective amount of at least one benzofuran or benzothiophene compound,or a pharmaceutically acceptable salt thereof, according to claim 15 incombination with a suitable excipient or pharmaceutical vehicle.
 62. Amethod for the treatment of arrhythmia or hypertension which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 1. 63. A method for the treatment ofarrhythmia or hypertension which comprises administering to a patient inneed of such treatment an effective amount of a compound according toclaim
 2. 64. A method for the treatment of arrhythima or hypertensionwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 3. 65. A method forthe treatment of arrhythmia or hypertension which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 4. 66. A method for the treatment ofarrhythmia or hypertension which comprises administering to a patient inneed of such treatment an effective amount of a compound according toclaim
 5. 67. A method for the treatment of arrhythmia or hypertensionwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 6. 68. A method forthe treatment arrhythima or hypertension which comprises administeringto a patient in need of such treatment an effective amount of a compoundaccording to claim
 7. 69. A method for the treatment arrhythmia orhypertension which comprises administering to a patient in need of suchtreatment an effective amount of a compound according to claim
 8. 70. Amethod for the treatment arrhythmia or hypertension which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 9. 71. A method for the treatment ofsuch arrhythmia or hypertension comprises administering to a patient inneed of such treatment an effective amount of a compound according toclaim
 10. 72. A method for the treatment of arrhythmia or hypertensionwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 11. 73. A method forthe treatment of arrhythmia or hypertension which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim
 12. 74. A method for the treatment ofarrhythmia or hypertension which comprises administering to a patient inneed of such treatment an effective amount of a compound according toclaim
 13. 75. A method for the treatment of arrhythmia or hypertensionwhich comprises administering to a patient in need of such treatment aneffective amount of a compound according to claim
 14. 76. A method forthe treatment of arrhythmia or hypertension which comprisesadministering to a patient in need of such treatment an effective amountof a compound according to claim 15.